FI121620B - Process for obtaining a controlled release formulation of an active substance - Google Patents

Abstract

The invention concerns controlled release oxycodone dosage forms comprising a multiparticulate system substrate comprising an amount of an oxycodone salt, the substrate being coated with an aqueous dispersion of at least one hydrophobic polymer, whereby the coating provides controlled release, the substrate including an additional dose of an oxycodone salt included in either the controlled release coating or in an additional overcoating coated on the outer surface of the controlled release coating, whereby the dosage forms, comprising the cured, coated substrate, comprise an effective amount of an oxycodone salt and provide a therapeutic effect for at least 12 hours when administered to a patient.

Description

METHODS FOR OBTAINING A CONTROLLED RELEASE FORMULATION OF THE ACTIVE SUBSTANCE An important aspect relating to the preparation, prescription and approval of all dosage forms relates to their long-term stability. The stability data obtained for a particular dosage form directly affects the shelf life of the dosage form. The stability of the pharmaceutical dosage form 10 relates to the preservation of its physical, chemical, microbiological, therapeutic and toxicological properties upon storage, i. in a special container and environment. Requirements for stability testing are set forth, for example, in Good Manufacturing 15 Practices (GMPs) and U.S.P, and in the regulations of a country applying for market approval of a dosage form. In the United States, a request for testing and possibly placing a drug or drug product on the market can be made through the New Drug Application (NDA), the Abbreviated New 20 Drug Application (ANDA), or the Investigational New Drug Applications (IND).

Agents used in sustained release dosage formulations often have particular problems with regard to their physical stability during storage. For example, the waxes used in such formulations are known to undergo physical changes during long periods of standing, so steps have been taken to stabilize them at the time of manufacture or to prevent them from changing. Fats and wax materials used in the pure state are known to crystallize in unstable forms, causing unpredictable changes in the amount of cc drug usefulness during stability testing C 1 g, during manufacture and later during storage.

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It is known that certain steps can be taken to obtain stabilized controlled release 2 formulations in many cases, such as ensuring that the individual agents are in a stable form before being mixed with the product and that process handling does not alter this state by increasing the instability by The additional additives and the dosage form of the individual substances are achieved in a stable state before the product is completely finished.

It is also known that the moisture content of a product can also affect the stability of the product. Changes in the hydration level of polymeric films, such as ethylcellulose films, can alter the amount of water permeability and utility of the drug. Binders such as gum arabic are also known to become less soluble when exposed to moisture and heat. However, the moisture content of the product can be controlled quite successfully using controls in the manufacturing process and by appropriate packaging of the product.

Previously, hydrophobic polymers such as certain cellulose derivatives, zeine, acrylic resins, waxes, higher aliphatic alcohols, and polylactic and polyglycolic acids have been used in the art to develop controlled release dosage forms. Methods of using these polymers to provide controlled release dosage forms such as tablets, capsules, suppositories, spheres, beads or microspheres involve coating individual dosage units from these hydrophobic polymers 1a. It is known in the prior art --- that these hydrophobic coatings can be applied either in LO 30 solution, suspension or dry. Because most of these

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Since the polymers are sparingly soluble in water, they are usually applied by dissolving the polymer in an organic solvent and spraying the solution on individual dosage forms (such as beads or tablets) and evaporating the solvent.

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Aqueous dispersions of hydrophobic polymers have been used in the prior art to coat pharmaceutical dosage forms for aesthetic reasons, such as film-coated tablets or beads, or to mask flavor. However, these dosage forms are used to release the active drug contained in the dosage form immediately.

The use of organic solvents in the preparation of hydrophobic coatings is considered undesirable due to inherent problems of flammability, carcinogenicity, environmental concern and safety in general. However, it has been highly desirable in the art to provide a controlled release coating derived from aqueous dispersions of a hydrophobic material such as ethylcellulose.

Unfortunately, to date, such formulations have not proven commercially feasible due to stability issues, although many formulations have been experimentally prepared based on a hydrophobic coating from an aqueous dispersion to release the active agent in a controlled manner. Aqueous polymer dispersions have been used to produce stable controlled release dosage forms, but this has only been possible by other methods, such as mixing said dispersions into a dosage form matrix, other than using an aqueous polymer dispersion coating to achieve slowing properties.

When coating using aqueous polymer dispersions to obtain a sustained release profile of the active agent (s) over a period of several hours or longer, it is known in the art that the dissolution release profile changes with aging; for example, when the coated final product is stored for a certain period of time, it may be exposed to high temperatures and / or humidity higher than ambient conditions. This problem is described, for example, in Dressman et al., Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 18 (1991), pages 654-655, Controlled Release Society, Inc., which reports that ethylpropylamine HCl pellets coated with a film based on ethylcellulose are stable only at room temperature under ambient humidity conditions. Munday et al., Drug Level, and Indus. Phar., 17 (15), 2135-2143 (1991), also reported that film-coated theophylline mini-tablets film-coated with ethyl cellulose and PEG (2: 1) and ethyl cellulose and Eudragit 15 L (2: 1). 1), inhibited dissolution during storage under stress, whereby the degree of retardation of release was said to be directly proportional to temperature, while the effect of relative humidity (RH) appeared to be insignificant. Munday et al. concluded that the reduction in release was due to a slower molecular diffusion of the drug through the polymer coating material and suggested that the change was due to significant changes in polymer permeability that occurred during experimental storage.

It is known that this instability problem does not occur when the polymers are applied from a solution of the organic solvent.

Thus, it is an object of the present invention to provide a controlled release tablet comprising a core containing an active agent, e.g.

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x an aqueous dispersion of a dense agent, disinfectant, cleaning agent, sterilizing agent and fertilizer, coated with an aqueous hydrophobic polymer, e.g. .

Another object of the present invention is to provide a controlled release preparation containing a large amount of inert beads containing an effective amount of the active agent, wherein the beads are coated with an aqueous dispersion of a hydrophobic polymer and provide reproducible stable dissolution despite being exposed to accelerated storage conditions.

Another object of the present invention is to provide a process for the manufacture of a controlled release tablet comprising a core comprising an active agent coated with an aqueous dispersion of a hydrophobic polymer such that the active agent has a stable dissolution profile when placed in the environment despite accelerated storage conditions.

Yet another object of the present invention is to provide a controlled release preparation comprising a substrate containing the active agent coated with an aqueous dispersion of a hydrophobic polymer such that the active agent has a stable dissolution profile when the formulation is placed in the environment, including after storage. the coated preparation may have been exposed to storage conditions where the temperature and / or humidity are greater than ambient conditions.

It is another object of this invention to provide a controlled release formulation wherein controlled release LO 30 is achieved by coating the formulation with an aqueous tr dispersion of a hydrophobic polymer such as ethylcellulose, wherein said coating produces the active agent contained in the formulation. stable dissolution

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5? in spite of the accelerated storage conditions, it was 35 that Tiina was an administrative supervisor such as the U.S. FDA, may consider dissolution acceptable for expiration date.

The foregoing objects and others are accomplished by the present invention, which relates to a partially controlled release preparation comprising a substrate containing an amount of the active agent sufficient to produce the desired effect in an environment of use wherein said substrate is coated with an aqueous dispersion of plasticized ethylcellulose. in an amount sufficient to achieve a controlled release of said active agent when contacted with said liquid. The coated substrate is cured at a temperature greater than the glass transition temperature of the aqueous dispersion of the plasticized ethylcellulose and at a relative humidity of about 60% to about 100% for a time sufficient to achieve an endpoint of curing, wherein said coated substrate provides is unchanged after exposure to accelerated storage conditions, wherein said endpoint is determined by comparing the dissolution profile of the preparation obtained immediately after curing with the dissolution profile of the preparation obtained after exposure to accelerated conditions, e.g., after 1-3 months at 37 ° C. temperature and 80% relative humidity. In certain preferred embodiments, the substrate o is coated so that its weight gain is from about 2 to about 25%.

In other embodiments, the coated substrate LO 30 is cured at a temperature greater than the glass transition temperature of the aqueous dispersion of the plasticized ethylcellulose and at a relative humidity of from about 60% to about 100% to provide a single ethylcellulose slurry of said coating. joining 05 35 and gradually slowing the release of said active agent when the product is exposed to environmental fluid until an end point is reached where the cured coated substrate, when reconstituted in vitro, releases said active agent in an amount that does not vary at any time along the dissolution curve more than about 20% of the total amount of active agent released compared to in vitro dissolution of said coated substrate prior to curing.

In still other embodiments of the invention, the cured preparation 10 provides a stabilized dissolution of said active agent, which is unchanged after exposure to accelerated storage conditions, with the United States Food & Drug Administration deeming it to be appropriate to grant expiration date of said preparation.

Other preferred embodiments relate to a controlled-release dosage form containing a substrate coated with an effective amount of an aqueous dispersion of ethylcellulose to achieve controlled release of the active agent, wherein said formulation, after being exposed to accelerated storage conditions for at least at a temperature of 75% relative humidity, the therapeutically active agent is released in an amount that at any given dissolution time does not vary by more than about 20% of the total amount of the therapeutically effective agent released compared to in vitro dissolution prior to storage.

In other embodiments, the coated substrate i LO 30, after being exposed to accelerated storage conditions in an in vitro dissolution assay, provides a bandwidth region not greater than about 20% at any instant. which compared to the dissolution profile before being exposed to the accelerated storage conditions.

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The active ingredient may be selected for a wide variety of uses including, but not limited to, systemically active therapeutic agents, topically active therapeutic agents, disinfectants, detergents, fragrances, fertilizers, deodorants, dyes, animal repellents, insecticides, pesticides, plant growth promoters.

The present invention further relates to a solid controlled-release oral dosage form comprising a substrate comprising a systemically active therapeutic agent in an amount sufficient to produce the desired therapeutic effect when taken orally. The substrate is coated with an aqueous dispersion of plasticized ethylcellulose and cured at a temperature greater than the glass transition temperature of the plasticized ethylcellulose aqueous dispersion and at a relative humidity of about 60% to about 100% for a time sufficient to provide controlled release of said active agent. measured by the USP Paddle Method at 100 rpm in 900 ml aqueous buffer (pH 1.6 -7.2) at 37 ° C, with about 5 to 42.5% (by weight) active after one hour, about 15-60% (w / w) of active substance had been released after two hours, about 17-75% (w / w) of active substance had been released after 4 hours, and about 20-90% % (by weight) of the active genuine 30 net was released after 8 hours, wherein said ci substrate is cured in said p ällysteessä indi-vidual cc etyyliselluloosahiukkasten interconnection cause the formation and release of said active agent to retard No gradually, as it has been exposed to (J) 35 to an environmental fluid until an endpoint is reached in which the release rate of 9 (e.g. in vitro dissolution) obtained after the cured, coated substrate has been exposed to accelerated storage conditions of 37 ° C and 80% relative humidity for 1-3 months is release rate obtained immediately after testing. Preferably, the dosage form produces a therapeutic effect for about 24 hours. The present invention further relates to a process for the preparation of a dosage form. The present invention also relates to a process for obtaining a controlled release formulation of an active agent, the method comprising preparing a solid substrate containing the active agent, coating the substrate with a sufficient amount of an aqueous dispersion of plasticized ethylcellulose and curing the coated substrate at a temperature greater than the glass transition temperature of the aqueous 20 aqueous dispersion of plasticized ethylcellulose and at a relative humidity of about 60% to 100% until an end point is reached where said coated substrate produces a stabilized solution of said active agent. exposed to accelerated conditions after being 25. The end point is determined, for example, by comparing the dissolution profile of the formulation immediately after curing with the dissolution profile of the formulation, obtained after exposure to accelerated conditions, whereby the accelerated conditions are m, for example 1-3 months at 37 ° C and 80%.

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x relative humidity.

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The present invention further relates to a method of treating a patient with a solid oral dosage form as described above. In this method, the present invention further includes administering to the patient an oral solid dosage form, said dosage form comprising a cured coated substrate to achieve the desired therapeutic effect for a period of about 12 to 24 hours. In particularly preferred embodiments, the oral solid dosage forms of this invention produce the desired therapeutic effect for about 24 hours.

The present invention provides many advantages over prior art coatings including, but not limited to, the avoidance of organic solvents with inherent safety concerns (flammability, carcinogenicity, environmental concern, safety in general) and extended stability which may result in longer life. 15 shelf life and the expiry date after which.

The following figures illustrate embodiments of the invention and are not intended to limit the scope of the invention as defined by the claims.

Figure A is a scanning electron micrograph (SEM) of a far-20 mass bead coated with a controlled release coating of this invention prior to curing.

Figure B is a scanning electron micrograph of the coated bead shown in Figure A after curing according to the present invention.

Fig. 1 is a graph showing the results of dissolution stability obtained in Example 1.

T-Figure 2 is a graph showing the results of the dissolution stability of Comparative Example i m 30 IA.

Fig. 3 is a graph showing the dissolution stability results of the comparative example cc IB.

Fig. 4 is a graph showing the results of dissolution stability of a comparative example.

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Fig. 5 is a graph showing the dissolution stability results of Example 1, comparing the dissolution profiles obtained under different conditions.

Figure 6 is a graph showing the first dissolution profiles obtained under various curing conditions.

Figure 7 is a graphical representation of the results obtained in Comparative Example 18A.

Figure 8 is a graphical representation of the results obtained in Example 18.

Figure 9 is a graphical representation of the results obtained in Example 19.

Figure 10 is a graphical representation of the results obtained in Example 21.

Figure 11 is a graph comparing the in vitro release of Examples 22 and 23 with a commercially available reference compound (MS Contin).

Figure 12 is a graph of blood levels of pi-20 obtained using the controlled release formulation of Examples 22 and 23 compared to the commercially available control compound (MS Contin).

Figure 13 is a graph of blood levels of pi-25 obtained when two 30 mg capsules of Example 23 were administered to a patient versus one o 30 mg MS Contin tablet.

Fig. 14 is a graph comparing

t— in vitro release of t-23 and 24 compared to MS

lq 30 to Contin.

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Figure 15 is a graph of blood levels for Examples 23 and 24 compared to MS Contin. Figure 16 is a graph of blood levels when two 12 mg 30 mg capsules of Example 24 were administered simultaneously to a single 30 mg MS Contin tablet.

Aqueous dispersions of hydrophobic polymers used as coatings in the present invention can be used to coat substrates such as tablets, spheres (or beads), microspheres, seeds, pellets, ion exchange resin beads, and other multiparticulate systems with the desired controlled release of active agent. Granules, spheres or pellets, etc., prepared according to the present invention may be administered in capsule or other suitable dosage form. The tablets of this invention may have any suitable shape, such as circular, oval, biconvex, hemispherical, any polygonal shape such as a square, a rectangle, and a pentagonal shape and the like.

To obtain a controlled release preparation, it is usually necessary to coat the active agent-containing substrate with sufficient aqueous dispersion of a hydrophobic polymer, e.g., ethylcellulose, such that the weight of the substrate increases by about 2 to 25%, although the coating may be less or more active. properties and desired rate of release, the plasticizer contained in the aqueous dispersion and how to incorporate it, for example.

The cured coated substrates of this invention provide a stable dissolution profile (e.g., in the environment of release of the active substance f) when stored for 30 hours at room temperature and ambient temperature.

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humidity (eg, long-term [real-time] tr testing) and has been investigated under accelerated storage conditions.

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The terms "stable dissolution profile" and "curing-end-35" are defined for purposes of the present invention 13 such that a cured coated substrate produces a reproducible release of the active agent when placed in an application environment where the release remains unchanged, even after cured coating. the substrate has been exposed to accelerated storage conditions. It will be understood by those skilled in the art that "unchanged" means that any change in the release of the active agent from the cured coated preparation may be considered to be insignificant in relation to the desired effect. In the case of pharmaceuticals, the stability decision is made, for example, by a regulatory body, such as the Food & Drug Administration (FDA) in the United States, to issue an expiration date.

15 The term "accelerated storage conditions" means, for example, storage conditions with a higher temperature and / or a higher relative humidity. Preferably, the term "accelerated storage conditions" refers to the storage conditions to which the final drug product is subjected to regulatory approval (e.g., FDA approval in the United States) and expiration date.

For purposes of the present invention, the term "expiration date" is defined as the date by which a batch of a product (e.g., a cured coated substrate) is expected to remain within the quality o values when stored under specified conditions, and thereafter should not be used ^.

i in 30 The term "bandwidth range" is defined in this

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for purposes of the invention, in contrast to in vitro dissolution measurements of controlled release cc release formulations, by comparing the dissolution profile (curve) obtained o o using the product after preparation 05 35 (before storage) and the dissolution profile 14 obtained after the coated product has been exposed to accelerated storage conditions, expressed as the percentage change in the amount of active substance released from the coated product at any time during the dissolution curve.

In general, the length of studies required by regulatory agencies, such as the FDA, and storage test conditions for pharmaceuticals are sufficient to cover storage, shipping, and subsequent use. The allowable storage test conditions may vary depending on the product details. For example, temperature sensitive drugs should be stored under alternative lower temperature conditions which are believed to be the temperature conditions for long term experimental storage. In such cases, it is generally accepted that accelerated testing should be conducted at a temperature of at least 15 ° C above this indicated long-term storage temperature with relative humidity conditions appropriate for this temperature.

20 The generally accepted accelerated assay used in FDA guidelines concerns the storage of a drug product (e.g., in a container or package) at 80% relative humidity and 37 ° C (1985 FDA Guidelines). For example, if the product lasts for three months under these 25 conditions (chemical stability, dissolution and physical properties), then the pharmaceutical product will be given an expiration date, for example, after two years. This accelerated test is now considered acceptable if it is performed at 75% relative humidity and 40 ° C (FDA Guidance 1987). Recently, it has been proposed that the long-term? Storage test be carried out for pharmaceutical preparations at a temperature of 25 ± 2 ° C and a relative humidity of at least 60 ± 5% for a trial period of at least 12 months. In addition, it has been suggested that 15 accelerated testing be performed on pharmaceuticals at a temperature of 40 ± 2 ° C and a relative humidity of 75 ± 5% for a period of at least 6 months. All of the above accelerated test criteria and others are considered equivalent for purposes of this invention with respect to determination of stability and determination of cure end point.

Controlled release coatings of the present invention include aqueous dispersions of hydrophobic polymers. Although ethylcellulose is a particularly preferred hydrophobic polymer for use as controlled release coatings of this invention, other hydrophobic cellulose derivatives (including other alkylcelluloses) may be used and are considered to be within the scope of the appended claims.

Incorporation of an effective amount of plasticizer into the aqueous dispersion of the hydrophobic polymer further enhances the physical properties of the film. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is necessary to plasticize ethylcellulose before using it as a coating material.

Plasticization of ethylcellulose can be accomplished using either so-called "internal plasticization" or "external plasticization". The suitability of the plasticizer depends on its affinity or solvating power to the polymer and its ability to interfere with the polymer-polymer bond. Such activity produces the desired flexibility of S 30 by reducing the stiffness of the molecule. Generally, the amount of plasticizer included in the coating solution is based on the amount of

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to the concentration, e.g. most often it is from about 1% to about 50% by weight of the film former. However, the concentration of the plasticizer can be suitably determined only after σ> 16 careful experimentation using the particular coating solution and application method.

An important parameter for determining a suitable plasticizer for a polymer relates to the glass transition temperature of the polymer 5 (Tg). The glass transition temperature refers to a temperature or temperature range whereby a fundamental change in the physical properties of the polymer occurs. This change does not reflect a change in state, but rather a change in the macromolecular mobility of the polymer.

Below 10 Tg, the mobility of the polymer chain is severely restricted. Thus, for a given polymer, if its Tg is above room temperature, the polymer behaves as a glass, making it hard, inflexible and quite brittle, properties that could be somewhat restrictive in a film coating, since the coated dosage form may be exposed to a certain amount of external ras.

The addition of suitable plasticizers to the polymer matrix effectively lowers the glass transition temperature so that, under ambient conditions, the films are softer, more flexible, and often stronger, and thus have better resistance to mechanical stress.

Other aspects of suitable plasticizers include the ability of the plasticizer to act as a good "blowing agent" for ethyl cellulose and the water insolubility of the plasticizer.

Examples of suitable plasticizable hydrophobic polymers (e.g., ethylcellulose) useful in the present invention include water-insoluble plasticizers such as dibutyl sebacate, di-ethyl phthalate, triethyl citrate, tributylcetate, tr and that other water-insoluble plasticizers may be used (such as acetylated monoglycerides, phthalate esters, castor oil-05 35, etc.). Triethyl citrate is a particularly preferred plasticizer for aqueous dispersions of ethylcellulose of this invention.

In addition, it has been found that the addition of a small amount of talc reduces the tendency of the aqueous dispersion to multiply during the process treatment and acts as a cleaning agent.

In one commercially available product, AquacoatR (an aqueous dispersion of ethylcellulose available from FMC Corp., Philadelphia, 10 Pennsylvania, USA), ethylcellulose is dissolved in a water-immiscible organic solvent and then emulsified in water as a surfactant and as a stabilizer. being. After homogenization, to obtain submicron-sized droplets, the organic solvent is evaporated in vacuo to form a pseudolatex. The plasticizer is not added to the pseudolatex during the manufacturing step. Thus, before use as a coating, it is necessary that the Aquacoat R be thoroughly mixed with a suitable plasticizer. Another aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pennsylvania, USA). This product is prepared by mixing the plasticizer into the dispersion during the manufacturing process. A hot melt of the polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to provide an aqueous dispersion that can be applied directly to the substrates.

^ Regarding handling and storage conditions in FMC

-A states that the viscosity of AquacoatR increases when it is exposed to < 15 ° C for a prolonged period.

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35 ° C, and that the viscosity can be reduced to less than 100 cps using shear (e.g., propeller type mixer). The FMC further states that a continuous film can be formed by a process known as gradual fusion, wherein 18 individual latex particles are joined together to form a continuous film of a plasticized ethylcellulose polymer. After this period, the properties are said to remain constant. The FMC mentions that higher coating temperatures of 5 lats or high temperature "curing" steps accelerate the process. The FMC notes that if the coupling process is not complete, the result will be a variation in release rates.

The stabilized controlled release formulations of this invention slowly release the active agent, e.g., when placed in an environmental fluid in the environment of use. By "environmental liquid" is meant that the preparation is placed in an aqueous solution (e.g., in vitro dissolution), in a simulated gastric fluid (e.g., USP Basket Method 15 (i.e., 37 ° C, 100 rpm, first hour, 700 ml gastric fluid, pH) 1.2, then 900 ml, pH 7.5) or gastrointestinal fluid (in vivo).

The controlled release profile of the formulations of the invention may be altered, for example, by varying the amount of coating of the aqueous dispersion of the hydrophobic polymer, changing the way the plasticizer is added to the aqueous dispersion of the hydrophobic polymer, changing the amount of plasticizer relative to the hydrophobic polymer, adding additional ingredients, and so on.

In a preferred embodiment of the present invention, the controlled-release dosage form comprises pharmaceutically acceptable beads (e.g., spheres) containing the active ingredient coated with a control-release release coating. The term sphere is known in the pharmaceutical art and means e.g.

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ground granules having a diameter of 0.2 to 2.5 mm, in particular 0.5 to 2 mm. A suitable commercially available example of such beads is nu pariel 18/20 35 beads.

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A large number of cured coated (stabilized) controlled release spheres can then be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose after ingestion and contact with gastric fluid.

Spheres or beads coated with a therapeutically active agent are prepared, for example, by dissolving the therapeutically active agent in water and then spraying the solution on a substrate, for example nu pariel 18/20 beads, using a Wurster insert. Optionally, additives are added to the solution prior to coating the beads to better bind the hydromorphone to the beads and / or to color the solution, etc. For example, a product containing hydroxypropylmethylcellulose and the like with or without dye may be added to the solution on the surface of the beads. The resulting coated substrate, in this example beads, may then optionally be coated with a barrier agent to separate the therapeutically active agent from the hydrophobic controlled release coating. An example of a suitable barrier agent is an agent containing hydroxypropyl methylcellulose (HPMC). However, any film former known in the art can be used. It is preferable that the dissolution rate of the final product o is not affected by the barrier.

The HPMC-protected (optional) beads of the hydromorphone can then be coated with a water-containing dispersion of the hydrophobic polymer or LO 30. The aqueous second dispersion of the hydrophobic polymer preferably further comprises an effective tr amount of plasticizer, e.g. triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose such as Aquacoat® and Surelease® can be used. If <j> 20 is used with SureleaseaR, adding a plasticizer separately is not necessary.

The coating solutions of this invention preferably contain, in addition to a film former, a plasticizer, and a solvent system (e.g., water) to provide a colorant and a product uniqueness. The dye may be added to the solution of the therapeutically active agent in place of or in addition to the aqueous dispersion of the hydrophobic polymer. For example, the dye can be added to Aquacoat R using color dispersions based on alcohol or propylene glycol, powdered aluminum lacquers, and an opacifier such as titanium dioxide, adding the dye to the water-soluble polymer, and then using a light cut to the plasticized Aquacoat R. Alternatively, any suitable method for producing color in the formulations of the present invention may be used. Suitable agents for coloring the preparation when using an aqueous dispersion of acrylic polymer include titanium dioxide and color pigments such as iron oxide pigment 20 titers. However, adding pigments can increase the retarding effect of the coating.

The plasticized aqueous dispersion of the hydrophobic polymer may be applied to the substrate containing the active agent by spraying using any suitable injection device known in the art. The preferred method employs a Wurster fluidized bed system, whereby an air nozzle that injects from below, fluidizes the core material and provides drying while the hydrophobic polymer coating is sprayed onto the surface.

Preferably, a sufficient amount of an aqueous dispersion of the hydrophobic polymer is applied to provide a predetermined controlled release of said cc active agent when subjected to exposure to said coated substrate, taking into account various factors such as the physical properties of the substance 21 and the mode of incorporation of the plasticizer. After the beads are coated with a hydrophobic polymer, a film-forming coating such as Opadry® may be applied to their beads. This coating, if any, is produced to substantially prevent bead aggregation.

Next, the coated beads are cured to obtain a stabilized release rate of the active agent.

Optimal cure values for temperature, humidity and time for a particular formulation are determined experimentally. In certain embodiments of the present invention, when the substrate refers to pharmaceutically acceptable beads coated with a drug, the beads coated with an aqueous dispersion of plasticized ethylcellulose are stabilized using a 15 curing oven at about 60 ° C and about 60-100%. at a relative humidity with a curing time of about 48 to 72 hours. This has been demonstrated for the hydromorphone beads described in the Examples below.

However, one skilled in the art will recognize that the necessary curing conditions will be affected by the particular drug contained in the formulation, as well as by the thickness of the controlled-release coating and the size of the substrate (e.g. beads compared to tablets).

In particular, it is possible that the time required for continuous curing to the end point described above may in fact be longer or shorter than the 48 to 72 hours mentioned above. Curing times which provide the intended result of the stabilized preparation are contemplated by LO 30 to be incorporated in the appended claims.

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circuit. Further, those skilled in the art will appreciate that the aqueous dispersion coated substrates of this invention may optionally be cured in some other manner to achieve an end point at which the coated substrate 05 35 provides a stable dissolution profile. Such other curing processes 22 which provide the intended result of the stabilized formulation are also considered to be within the scope of the appended claims.

The curing endpoint may be determined by comparing the dissolution profile of the cured coated substrate (e.g., "formulation") obtained immediately after curing (hereinafter "first dissolution profile" or "initial dissolution profile") with the formulation obtained after exposure. -10 for storage conditions. Generally, the end point of curing can be determined by comparing the dissolution profile of the preparation after exposure to accelerated storage conditions, e.g., 37 ° C / 80% RH or 40 ° C / 75% relative humidity for one month, to the first dissolution profile. However, the cure endpoint may be further determined by further exposing the cured coated preparation to accelerated storage conditions and comparing the dissolution profile of the finished product obtained after, e.g., 2 and / or 3 months exposure to the first obtained dissolution profile.

In certain preferred embodiments of the present invention where the cured coated substrate is a far-25 bulk preparation, the curing end point is reached when the data points plotted along the dissolution curve obtained e.g. after the product has been subjected to accelerated conditions 1-3 months, indicate release of the active agent, which at any given time does not vary by more than about 20% of the total amount of active agent released relative to in vitro dissolution prior to storage. Such a difference in the in vitro dissolution curves, which

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In the art, termed "band variation range" or "band le- σ> 35 water", for example, is 20%. Generally, when in vitro dissolution prior to storage and after exposure to accelerated conditions does not vary, e.g., up to about 20% of the total amount of active agent released, the preparation is considered to be approved by governmental control agencies such as U.S. Pat. As assessed by the FDA for stability and expiration date. The FDA defines acceptable bandwidths on a case-by-case basis and any bandwidth band for a particular drug that is considered acceptable by such an administrative control body is included in the appended claims. In preferred embodiments, the aforementioned band range is up to 15% of the total amount of active agent released. In more preferred embodiments, the band variation range is up to 10% of the total amount of active agent released. In the accompanying examples, the bandwidth range is often significantly less than 10%.

Further, the release of the active substance from the controlled release preparation of the present invention may be affected, i. adjust to the desired rate by adding one or more release modifiers or by providing one or more passageways through the coating.

Release modifiers that act as pore formers may be inorganic or organic and include substances that can be dissolved, extracted or rinsed from the coating in the environment of use. For example, pore formers may comprise the release of one or more aqueous hydrophilic polymer A preparations. There are 30 hydrophilic polymers suitable for the label.

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such as hydroxypropylmethylcellulose, cellulose ethers, acrylic resins and protein-derived substances. Of these polymers, cellulose ethers, especially hydroxy-1-4 alkyl celluloses and carboxyalkyl celluloses, are σ> 35 preferred. Synthetic water-soluble polymers such as polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, etc., and polysaccharides, e.g., pullulan, dextran, etc. may also be used.

In addition, water-soluble polydextrose, which is at least about 1% water-soluble (w / w) at 25 ° C, may be added in a controlled manner to the substance-releasing coating.

Pore formers also include alkali metal salts, polysaccharides such as lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate, sodium citrate and the like. Suitable polysaccharides include sucrose, glucose, fructose, mannitol, lactose, mannose, galactose, sorbitol and the like. The pore-forming solids may also be polymers which are soluble in the environment of use, such as Carbowaxes R, Carbopol R 20 and the like. The pore former includes diols, polyols, polyhydric alcohols, polyalkylene glycols, polyglycols, poly (a-w) alkylenediol and the like. The pore formers are non-toxic and their removal from devices, ducts, and pores is through lamellae filled with liquid present in the operating environment.

Semi-permeable polymers can also be added to a cm controlled release coating to alter the release properties of the fertilizer. Such semi-permeable polymers include, for example, cellulose acylate, cellulose diacylate, cellulose triacrylate, cellulose acetate, cellulose diacetate, cm cellulose triacetate, beta-glucan acetate, acetaldehyde.

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hydridomethyl acetate, cellulose acetate, ethyl carbamate, polyamide, polyurethane, sulfonated polystyrene, cellulose acetate phthalate, cellulose acetate methylcarbamate, cellulose acetate succinate acetate, cellulose acetate acetate duloxetate, cellulose acetate acetate tannate, cellulose dipentanate, cellulose dipentanate, cellulose acetate valerate, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, and other semipermeable polymers such as those described in U.S. Patent No. 4,285,987. as well as selective permeable polymers formed by co-precipitation of a polycation and a polyanion, as disclosed in U.S. Patent Nos. 3,173,876, 3,276,586, 3,541,005, 3,541,006 and 3,546,142 (incorporated herein by reference). ).

Controlled release coatings of this invention may also include other release modifiers, such as cellulose acetate phthalate, and the agents described in U.S. Patent No. 2,196,768, which is incorporated herein by reference. Other suitable release control agents that may be included in the controlled release coating of the present invention include shellac, zein, hydroxypropylmethylcellulose phthalate, sandarwood, modified shellac, and the like.

The controlled release coatings of this invention may also include released modifying agents that promote erosion (i.e., erosion promoting agents) such as starch (including, but not limited to, corn starch, rice starch, m 30 a- starch, carboxymethyl starch, potato starch and

CM

other vegetable starches), modified starches and starch derivatives. This group is also intended to include other erosion promoting agents such as, but not limited to, xanthan gum, alginic acid 35, other alginates, bentonite, veegum, 26 agar, guar gum, locust bean gum, gum arabic, quittenipsyllium, linseed, ocher gum, arabino-lactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, etc., crosslinked polyvinylpyrrolidone, ionopyrrolidone, carrageenan, kappa-carrageenan, lambda-carrageenan, karaya gum, biosynthetic gum, etc.

Controlled release coatings of this invention may also include release modifying agents useful for the preparation of microporous lamellae in an environment of use, such as polycarbonates consisting of linear polyesters of carbonic acid having carbonate groups re Phosphorylated dihydroxyl aromatic such as bisphenol, microporous poly (vinyl chloride), microporous polyamides such as polyhexamethylene adipamide, microporous modacrylic copolymers including polymers of poly (vinyl containing diphenylene sulfone in a linear chain, halogenated poly (vinylidene), polychloroethers, acetal polymers, polyesters produced by esterification of dicarboxyl-25 ha ppo or anhydride with alkylene polyol, poly (alkylene sulfides), phenols, polyesters, microporous poly-o-saccharides with substituted hydroglucose units and with reduced permeability to water and biological fluid passageways, asymmetric porous polymers, or hydrophilic microporous homopolymers, copolymers or cc interpolymers with reduced bulk density, and the agents described in U.S. Patent Nos. 3,595,752, §3,643,178, 3,654,066, 3,709,774, 3 718,532; 3,803,601; ω 35 3,852,224; 3,852,388; and 3,853,601 (all of which are incorporated by reference herein) and in GB Patent No. 1,126,849 and Chera. Abstr. Oh. 71, 427F, 22573F, 1969.

Other microporous materials to form microporous la-Mell include poly (urethane), crosslinked, extended chain poly (urethane), poly (imides), poly (benzimidazoles), collodion, regenerated proteins, semi-solid crosslinked poly (vinyl) doni), microporous materials prepared by diffusion of polyvalent cations into polyelectro-lithium sols, microporous derivatives of poly (styrene) such as poly (sodium styrene sulfonate), poly (vinylbenzyltrimethylammonium chloride), microporous microporous cellulose, polymers disclosed in U.S. Patent Nos. 15,524,753, 3,556,559, 3,276,589, 3,541,055, 3,541,006, 3,546,142, 3,615,024, 3,564,178 and 3,585,224 (all of which are incorporated herein by reference) for reference).

In certain preferred embodiments of the present invention, the release modifying agent is hydroxypropyl methyl 20 cellulose, lactose, metal stearate or a mixture thereof.

Generally, the amount of release modifier contained in the controlled release coatings of the present invention may be from about 0.1 to about 80 weight percent, based on the combined weight of the hydrophobic polymer (e.g., ethylcellulose) and release modifier, and generally the hydrophobic polymer and hydrophilic the ratio of polymer to polymer is about 99: 1 to about 20:80 by weight. In certain preferred embodiments, the roll release formulations of the container 30 of this invention contain about

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x 0.1 to 50 wt.%, and in most preferred embodiments, about 0.1 to 25 wt. the combined weight of the hydrophobic polymer and release modifier o.

The controlled-release coatings of this invention may also include an escape section comprising at least one passageway, opening, or the like. The passageway may be formed using the methods disclosed in U.S. Patent Nos. 3,845,770, 3,916,889, 4,063,064 and 4,088,864 (all of which are incorporated herein by reference). The corridor can have any shape, such as round, triangular, square, elliptical, irregular, etc.

The active ingredient (s) contained in the controlled-release formulations of the present invention includes systematically active therapeutic agents, topically active therapeutic agents, disinfectants, chemical impregnants, detergents, deodorants, fragrances, colorants, animal-repellents, fertilizers, pesticides, herbicides, fungicides and plant growth promoters and the like.

A wide variety of therapeutically active agents may be used in the present invention. Therapeutically active agents (e.g., pharmaceutical agents) which may be used in the compositions of this invention include both water soluble and water insoluble drugs. Examples of such therapeutically active agents include antihistamines (e.g., di-menhydrinate, diphenhydramine, chlorpheniramine and o-dexchloropheniramine maleate), analgesics (e.g., aspirin, codeine, morphine, dihydromorphone, oxycodone A, etc.). -inflammatory agents (e.g.

io 30 naproxen, diclofenac, indomethacin, ibuprofen,

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sulindac), anti-emetic agents (e.g., methococ-clopramide), antiepileptic drugs (e.g., phenytoin, meprobabate and nitriczepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine), cough - 05 35 anti-irritants and anti-mucus agents (codeine phosphate), asthma-control agents (eg theophylline), acid medications, antispasmodics (eg atropine, scopolamine), antidiabetic agents (eg insulin), urine secretagogues (e.g. eta-5 cryic acid, co-fluazide), antihypertensive agents (eg propranolol, clonidine), antihypertensive agents (eg clonidine, methyldopa), bronchodilators (eg albuterol), steroids (e.g. -10 ni, prednisone), antibiotics (eg tetracycline), antihypertensives, hypnotics, psychotropic drugs, diarrhea harvests, mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants (including 15 appetite suppressants such as phenylpropanolamine). The above list is not intended to be exclusive.

In certain preferred embodiments, the therapeutically active agent comprises hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, salts of any of the foregoing, mixtures of any of the foregoing, and the like.

In another preferred embodiment of the present invention, the active agent is a topically active therapeutic agent and the environment of use may be, for example, the gastrointestinal tract or bodily cavities such as the oral cavity, pockets associated with tooth decay, surgical wounds, rectum or vagina.

The topically active pharmaceutical ingredient (s) comprises antifungal agents (e.g.

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amphotericin B, clotrimazole, nystatin, ketoconazole,? miconazole, etc.), antibiotic agents (penicillins, cephalosporins, erythromycin, tetracycline, aminoglyco-co-binders, etc.), antiviral agents (e.g., acyclovir, 05 35 idoxuridine, etc.), (eg chlorophyll), antitussives (eg dextromothorphan hydrochloride), dental caries (eg fluoride metal salts, sodium monofluorophosphate, tin (2) fluoride, amine fluorides), analgesics (e.g.

5 methyl salicylate, salicylic acid, etc.), local anesthetics (eg benzocaine), oral antiseptics (eg chlorhexidine and its salts, hexylresorcinol, dequinium chloride, cetylpyridinium chloride), anti-inflammatory agents (e.g. , triamcinolone, hydrocortisone, etc.), hormonal agents (estriol), anti-plaque agents (e.g. chlorhexidine and its salts, octenidine and mixtures of thymol, menthol, methyl salicylate, eucalyptol), acidifying agents (e.g., buffers). , calcium carbonate, sodium bicarbonate, sodium and potassium hydroxide, etc.), dental hypersensitivity agents (e.g. potassium nitrate). This list is not intended to be exclusive.

When the controlled-release coating of this invention is to be used in tablets, the tablet core (eg, substrate) may contain the active ingredient together with any pharmaceutically acceptable inert pharmaceutical excipient (diluent) including, but not limited to, sucrose, dextrose. , lactose, microcrystalline cellulose, xylitol, o-fructose, sorbitol, mixtures of the above and the like. Also, an effective amount of any commonly accepted pharmaceutical lubricant, including calcium and magnesium soaps, may be added as described above.

(OF

to the excipients prior to forming the tablet core-

CC

extrusion of substances. Most preferred is magnesium stearate in an amount of about 0.2 to 3% by weight of the solid $ 2 dosage form.

In another preferred embodiment of the present invention, the active agent is a disinfectant, e.g., a chlorine compound such as calcium hypochlorite, and the environment of use is a structure surrounding the water, e.g., a recreational pool.

In yet another preferred embodiment of the present invention, the active agent comprises at least one of a detergent, a bactericidal agent, a deodorant, a surfactant, a fragrance, a perfume, a sterilizing agent and / or a dye, and the use medium is an aqueous solution, e.g. . Urinal or WC.

In yet another preferred embodiment of the present invention, the active agent is a chemical impregnator, e.g. fertilizer, animal repellents, insect repellents, pesticides, herbicides, fungicides, plant growth promoters, and the environment is e.g. The fertilizer may be, for example, a nitrogen-containing compound such as urea, urea-formaldehyde composites, potassium nitrate, potassium sulfate, potassium chloride, ammonium nitrate, ammonium sulfate, mono-20 ammonium phosphate, dibasic ammonium phosphate, ammonium superphosphine, , boron, molybdenum, and mixtures of any of the foregoing. For example, the fertilizer may be in granular form.

For example, when the coated substrate is a coated chlorine tablet to combat bacterial and algae contamination in swimming pools and the like, the substrate may contain commercial grade calcium hypochlorite, trichloroisocyanuric acid, sodium dichlorochloride, with or without the like, cc “For example, the substrate may contain about 98.5% by weight of commercial grade calcium hypochlorite and

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^ 1.5% by weight of ground lime. The substrate may also contain commercial granular calcium hypochlorite, up to 32% by weight of calcium chloride and 1% zinc stearate, with a usable chlorine content of about 69% and a weight of about 57 g and a diameter of about 40 mm, as described in U.S. Pat. Patent 4,192,763, which is incorporated herein by reference. The substrate is then coated with an aqueous dispersion of the plasticized hydrophobic polymer so as to increase its weight by about 3 to 30% depending on the desired dissolution rate, and then the coated tablet is cured according to the present invention until the end point at which the cured coated tablet is reproducibly produced.

When the active ingredient comprises a composition suitable for cleaning and preventing the lavatory basins, the substrate may contain a well-known disinfectant such as calcium hypochlorite and / or trichloroisocyanuric acid. Alternatively, the active ingredient may comprise an alkali metal salt of dichloroisocyanuric acid and a chloride salt such as calcium chloride and barium chloride, as in the product described in U.S. Patent 4,654,341, which is incorporated herein by reference.

One possible example of such a product could include a substrate containing 0.5 to 5% fragrance, 1 to 10% dye, 10 to 40% surfactant (which may be nonionic, cationic, anionic or amphoteric surfactant) and other possible ingredients, such as bactericidal agents, disinfectants, process aids, and other commonly incorporated substances known to those skilled in the art. Such active

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The excipients may be included in a substrate that handles the tablet, other well-known ingredients such as detergents, surfactants, perfumes,

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excipients and any necessary excipients 35.

33

Alternatively, the substrate may also comprise a pellet prepared by homogeneous mixing of, for example, 1 g of sky blue dye 65% (a dye commercially available from Hilton David), 1 g of 5 Pluronic F-127 (a nonionic surfactant, containing condensation products of ethylene oxide with the product resulting from the reaction of propylene oxide with ethylenediamine, commercially available from BASF-Wyandote Chemicals, 38 g of 10 Carbowax 8000 (solid polyethylene glycol, molecular weight 8000; commercially available from C) ) and 40 g of Kemamide U (oleylamide surfactant; commercially available from Witco) and a possible fragrance (e.g., 0.5% by weight of citrus-pine-15 fragrance) followed by a mixture of the above pellets by conventional methods such as noodling, plodding, extruding and cutting and stamping mas sa to form pellets. Optionally, the pellets may also contain a suitable amount of inorganic salts to deposit the pellets at the bottom of the container and one or more binders, such as guar gum. The pellet is then coated with an aqueous dispersion of the plasticized hydrophobic polymer so that its weight increases by about 2 to 30% depending on the desired dissolution rate, and then the coated pellet is cured according to the present invention until the end point at which the cured coated pellet is stable.

Another example of a substrate useful for treating Vessels Rinse Water is a substrate containing an iodophor such as povidone iodine,

CC

as described in U.S. Patent 5,043,090, incorporated herein by reference, p

That is, when the substrate contains a fragrance, the fragrance 35 may be any commercially available paraffin oil, e.g., volatile compounds including esters, ethers, aldehydes, alcohols, unsaturated hydrocarbons, terpenes and other substances well known in the art. Their type and compatibility are limited only by their compatibility and desirability as may be determined by those skilled in the art.

When the active agent comprises a composition suitable for use as a fertilizer, the active agent may comprise granular urea, which is coated with an aqueous dispersion of the plasticized hydrophobic polymer to increase its weight by about 2 to 30%, and then cured according to the present invention. In the production of a urea pill, urea with a solids concentration in water of 70% is substantially heated to substantially remove the water. The molten urea is then injected into droplets into an air cooling tower which forms crystallized urea as a hard pill or bead, which is then coated and cured in accordance with the present invention.

When the substrate comprises plant nutrient preparations, the substrate may be pelletized in spherical, fine or sticky form and may further contain growth promoters such as gibberellic acid in combination with soil antifungal agents such as formaldehyde and paraformaldehyde, etc.

In certain embodiments of the present invention, the coated substrate contains an additional dose of the active agent contained in either a controlled release coating consisting of an aqueous dispersion of a hydrophobic polymer or an additional coating of a controlled release formulation.

(M

x on the outside of the scorching coating. This may be desirable when, for example, a dose of a therapeutically active agent is required to produce therapeutically effective concentrations of the active agent in the blood when the preparation is first exposed to gastric fluid σ> 35.

35

Figure A is a scanning electron micrograph (SEM) of a theophylline bead coated according to the present invention prior to curing at a magnification of 18,000. The coating is an aqueous dis-5 pers of ethyl cellulose, the coating of which increased by 5% by weight. SEM shows clearly distinguishable particles of ethylcellulose on the coating surface. Due to cracks or pores in the coating, the coating allows the surrounding fluid to enter the underlying core with the active agent.

Figure B is a scanning electron micrograph (SEM) of the theophylline bead shown in Figure A after curing the bead in an oven at 60 ° C and about 85% relative humidity for 72 hours. The SEM of Figure B is magnified at 15,000. The individual ethylcellulose particles 15 are joined and fused to such an extent that they remain exposed to temperatures above the glass dispersion temperature of the aqueous dispersion and no longer cause fusion or relative humidity to about 60-100% RH. , which would alter the dissolution profile of the further coated substrate.

The following examples illustrate various aspects of the present invention. They should not be construed as limiting the claims in any way. In the results of the dissolution tests of the following tablets, the underlined numbers and the numbers shown in the columns below these underlined numbers represent the percentage of active ingredient dissolved.

Example 1A Hydromorphone beads were prepared by dissolving hydro-romorphone HCl in water by adding Opadry® Y-5-1442, light pink (product commercially available from cc).

Coloron, West Point, Pennsylvania, and containing hydroxypropylmethylcellulose, hydroxypropylcellulose, titanium dioxide, polyethylene glycol, and D&C REd No.

35% Aluminum Lake, 20% by weight, and mixing mixture 36 for about 1 hour and then spraying it onto nu pariel 18/20 beads using a Wuster insert. The resulting coated beads were then coated with Opadry® Y-5-1442 pink (15% by weight). The preparation obtained as Tu-5 had the formulation shown in Table 1 below.

table 1

Ingredient% Quantity / Unit 10 Hydromorphone HCl 4.75 4 mg nu pariel 18/20 87.9 74 mg

OpadryR Lt. Pink Y-5-1442 2.4 2 mg

Opadry® (coating) 5.0 4.2 mg 15 Total 100.0 84.2 mg

The HPMC-protected beads of hydromorphone were then coated with 15% by weight of AquacoatR (containing triethyl citrate) and then, after curing, coated with 5% by weight of OpadryR Light Pink (see Table 2). The high moisture cured beads were dried in the fluidized bed before the final coating.

Table 2 - Composition after Coating 25 Ingredient Percent

Hydromorphone Beads 80.57 o Aquacoat R ECD 30 12.06

Triethyl Citrate 2.39 ^ OpadryR Lt. Pink 4.98 ιΑ 30 Y-5-1442 (coating) 100.00

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X

cc

The product was then divided into four portions. In Example 1, the coated beads were placed in a 30 cm 3 amber glass vial and cured in an oven for 72 hours at 60 ° C and 85% relative humidity. In Comparative Example IA, the coated beads were cured for 24 hours at 60 ° C under dry conditions. In Comparative Example IB, the coated beads were cured for 72 hours at 60 ° C in a dry condition. In Comparative Example 1C, coated beads were cured for 24 hours at 60 ° C and 85% relative humidity.

For all products cured under the various conditions mentioned above, the stability under the following conditions was investigated: at room temperature, at 37 ° C, dry; At 37 ° C / 85% relative humidity (RH); At 50 ° C in a dry state; and 60 ° C / 85% RH.

The relative humidity in a water-filled drying apparatus at 60 ° C in an oven was determined by first pouring about 500 g of purified water into a plastic drying apparatus and adding a metal cap. Place the hygrometer / temperature indicator on the cover and cover the drying apparatus and place it in a oven at 60 ° C for 20 hours for 24 hours. Then, after 24 hours, the relative humidity in the dryer was 85% while the temperature was still 60 ° C. When the hygrometer alone was placed in an oven at 60 ° C for 24 hours, the relative humidity was 9% at 60 ° C.

Dissolution experiments were performed using USP Basket

Method, 37 ° C, 100 rpm, first hour 700 700 ml of gastric fluid at pH 1.2, then change to 900 900 ml at pH 7.5. In all cases t! dissolution was accomplished by placing an open capsule containing a specified amount of cured beads (8 mg

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hydromorphone HCl, 208 mg beads ± 10%).

cc o- It was observed that the dissolution of Example 1 did not change under these accelerated conditions except that the ha-ooo avoided changes under extreme conditions which were 60 ° C / 85% relative humidity.

38

The results of Example 1 are shown in the following Tables 3-8.

Table 3 - At room temperature 5 Hydromor-

Time background HCl Dissolution (wk) (volume) 12 4 1 H 18 24

Beginning 8.14 mg 0 4f6 29T5 52, 6 64.7 76.6 82.8 1 7.95 mg 0 5.1 30.3 55.0 67.4 79.8 88.9 1 (^ 4 7, 80 mg 1.3 8.2 33.5 57.4 70.0 82.8 90.9 8 7.78 mg 0.7 6.0 30.5 54.0 66.4 78.0 88.2

Table 4 - 37 ° C in dry conditions

hydromorphone

Time background HCl Dissolution 15 (wk) (volume) 114, 8 12 18 24

Beginning 8.14 mg 0 4.6 29.5 52.6 64.7 76.6 82.8 1 7.96 mg 0 6.0 30.8 55.3 68.0 81.6 89.7 4 7 , 91 mg 2 8.1 33.2 56.6 70.2 82.0 91.3 8 7.73 mg 1 5.8 31.3 57.5 64.6 82.7 91.6 20 Table 5- 37 ° C and 80% relative humidity

hydromorphone

Time Background HCl Dissolution (wk) (Amount) 1 2 4 8 11 and li

Beginning 8.19 mg 0 4.6 29.5 52.6 64.7 76.6 82.8 1 7.85 mg 0 5.6 31.0 55.1 68.5 80.3 89.1 4 8 , 16 mg 2.4 7.6 32.3 52.8 64.4 75.4 82.7 ° 8 8.22 mg 2.9 7.9 33.5 53.3 64.5 73.6 81, 3

(M

-A Table at 6-50 ° C (dry) ^ Hydromor-

Time background HCl Dissolution | (wk) (quantity) il i 8 12 18 24

Beginning 8.14 mg 0 4.6 29.5 52.6 64.7 76.6 82.8 o 1 8.14 mg 0 6.3 32.7 56.3 68.3 80.8 89 S 35 4 7.81 mg 2.3 10 37.0 59.6 72.0 84.5 92 8 7.74 mg 2 10.4 35.8 59.2 71.3 82.3 90.5

Table at 7-60 ° C (dry)

hydromorphone

Time background HCl Dissolution (wk) (volume) 12 1 8 12 18 24 5 Beginning 8.14 mg 0 4.6 29.5 52.6 64.7 76.6 82.8 1 8.13 mg 0 6, 7 34.6 57.8 70.3 82.1 90.5 4 8.30 mg 2.7 10.6 36.6 56.8 68.7 80.4 85.6 8 7.94 mg 3.6 11.9 37.4 58.4 71.1 80.6 89.3

Table at 8-60 ° C and 100% relative humidity

hydromorphone

Time background HCl Dissolution (wk) (Amount) 1 2 1 8 12 18 18 24

Beginning 8.14 mg 0 4.6 29.5 52.6 64.7 76.6 82.8 15 1 7.26 mg 6.1 9.9 23.4 42.4 53.3 63.1 72, 5 4 6.64 mg 19 23.7 32.5 41.4 46,, 7 53.0 51.7 8 5.38 mg 25.1 28.4 33.2 40.0 44.1 47.7 52 , 0

The data presented in Table 5 show that despite being exposed to accelerated conditions, the change in the amount of hydromorphone released at each time point was insignificant. The greatest lane variation occurred at the moment 24 hours (after two months of storage), with a difference of 1.5% in the amount released.

In contrast, the dissolution profiles of Comparative Examples IA, IB and 1C showed continuous deceleration (eg curing) under all accelerated conditions.

The results are shown in Tables 9, 10, and 11. The widest point of the Comparative Example IA bandwidth was 22.4% -A (4 hours dissolution). The widest point of the band of comparative Example IB was 17.3% (solubility 12

C \ J

h). In contrast, the widest point of the £ 1 band of comparative Example 1C was only 9.1% (18 hours dissolution). The fact that the results ro of Comparative Example 1C represents a significant improvement over that of Comparative 05 35 Examples IA and IB is not surprising since 40 was the only comparative example using curing at high relative humidity conditions.

Table 9 - Comparative Example IA

K

hydromorphone

Time background HCl Dissolution (wk) (volume) 1 2 4 8 12 18 24

Beginning 9, 03 mg 17.8 43.6 63.6 78.8 86.7 94.7 94.2

At room temperature ^ 8 wk 8.79 mg 18.4 35.9 58.2 76.3 88.7 97 * 37 ° C (dry) 8 wk 8.50 mg 14 36.5 59.1 81.1 91 , 4 99.4 * 37 ° C / rel. 80% 8 wk 8.15 mg 6.6 23.6 41.2 60.7 72.3 83.1 * 50 ° C (dry) 15 8 wk 8.45 rng 17.3 36 56.1 78 , 1 89, ^ 97.1 102.6 at 60 ° C (dry) 8 wk · 8.65 mg 7.3 28.5 48.9 64.4 82 92.3 99.1 60 ° C / rel. .kost. 100% 20. 8 Vk 5.81 mg 17.5 22.6 28.8 36.5 41.7 46.5 50.3

Table 10 - Comparative Example IB

hydromorphone

Time background HCl Dissolution (wk) (volume) 1 2. 4. 8 12. 18 24.

25 Initial 8.82 mg 4.7 35.5 58.3 75.6 87.3 96.0 98.2

At room temperature 8 weeks 8.29 mg 8.7 34.6 59.3 80.8 92.1 99.2 105.7 5 at 37 ° C (dry) ™ 8 weeks 8.34 mg 8.3 36.1 55.9 77.4 87.3 97.8 103.1 ^ is at 37 ° C / rel. 80% to 30 ™ 8 wk 8.86 mg 4.9 25.4 43.6 61.7 70 80 87.2 x £ 50 ° C (dry) CM 8 wk 8.71 rg 10.8 35, 4 55.9 77.2 88.9 99.5 103.2 CM '60 ° C (dry) ^ gg 8 wk 8.30 mg 5.3 32 54.1 76.6 87.2 99, 8 105.5 at 60 ° C / rel. 100% 8 wk 6.22 mg 16.3 21.2 27.4 35.9 40.5 46.2 49.4

Table 11 - Comparative Example 1C

41

hydromorphone

Time background HCl Dissolution (wk) (volume) 1 2 4 8 12 18 24

Beginning 8 f 71 mg 0.7 15.3 41.9 60.7 71.2 82.4 86.7 5

At room temperature 8 weeks 8.40 mg 1 14.2 39.8 58.8 69.1 79.1 87.2 at 37 ° C (dry) 8 weeks 8.84 mg 2.7 14.5 40.5 60 , 4 71 81.3 89.8 at 37 ° C / rel. 80% 10 8 wk 8.78 mg 2.5 12.4 37.8 54.6 63.8 73.3 * 50 ° C (dry) 8 wk 8.71 mg 3.2 17.5 42.3 61 , 1,70.8 81 87.9 at 60 ° C (dry) 8 wk 8.57 mg 2.9 18.2 43.4 62.5 73.6 84.3 * 60 ° C / rel. 100%> 8 wk 6.10 mg 15.7 20.3 26.4 33.8 38.3 43.1 46.7

Figure 1 is a graph of the dissolution results obtained in Example 1, comparing the first dissolution profile with the dissolution profile after 8 weeks of storage at 37 ° C / 85% RH.

Figure 2 is a graph of the dissolution profile of Comparative Example IA comparing the first dissolution profile with the dissolution profile after 8 weeks of storage at 37 ° C / 80% RH.

Fig. 3 is a graph of the dissolution profile of Comparative Example ° IB versus first dissolution profile of τΐ after 8 weeks of storage at 37 ° C / 80% RH. .

Figure 4 is a graph of the dissolution profile of Comparative Example 1C compared to the dissolution profile after 8 weeks storage at 37 ° C / 80% RH.

Comparing the results shown in Figure 1 (Example 1) with the results shown in Figures 2-4 (Comparative 5 Examples), it is immediately apparent that only in Example 1 the dissolution profiles of the first and 8 weeks were essentially similar under storage conditions of 37 ° C and humidity 80%.

Figure 5 is a graph of the dissolution profiles of Example 1 versus the first dissolution profile of the dissolution profile after 8 weeks of storage under various conditions (room temperature; 37 ° C / 80% relative humidity; and 60 ° C in dry). It is seen that the dissolution profiles of Example 1 after 8 weeks under these different conditions are substantially identical.

Finally, Figure 6 is a graph of first dissolution profiles obtained after various curing conditions [curing for 2 hours at 60 ° C in dry (prior art); 72 hours at 60 ° C / 85% RH (Example 1); 24 hours at 60 ° C in dry (Comparative Example IA); 72 hours at 60 ° C in dry (Comparative Example IB); and 60 ° C at -25% at 85% relative humidity for 24 hours (Comparative Example 1C)] o Example 2 3 Curing at 60 ° C Dry Heat - Longer A Drying In Example 2, beads were made

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according to Example 1, to determine whether the stabilized first dissolution obtained after curing at 60 ° C and 85% 00 relative humidity, instead, achieves a longer drying time without humidity. . The beads were coated with Aquacoat, followed by a further application of Opadry® Y-5-1442 pink. The coated product had the composition shown in Table 12 below.

5

Table 12 - Composition after Coating.

Substance% Quantity / unit

Hydromorphone beads 80.57 84.2 mg

AquacoatR ECD 30 12.06 12.6 mg 10 I Triethyl citrate 2.39 2.5 mg

OpadryR Lt. Pink (coating) 4.98 5.2 mg 100.0 99.3 mg

The hydromorphone HCl-15 beads coated with AquacoatR were then cured at 60 ° C in a dry oven and stored at 60 ° C dry temperature. The cured beads were placed in open gelatin capsules with a fixed amount of cured beads per capsule (about 8 mg hydromorphone HCl) and the dissolution studies were then performed as shown in Example 1 using three samples at: 1 day, 2 days days, 7 days, and 21 days to determine the stability of the dissolution profile. Dissolution studies were performed, as detailed above, using three samples. The average results are shown in Table 13 below.

o o Table 13 i ^ Dissolution (time) '30

Time Weight Hours (dd) (mg) 1 2 4 8 12 18 24 £ Beginning 196r 7 15.6 43.8 68.8 89.9 101.0 109.2 113.8 £ 1 196.3 3.7 37.5 63.5 84.9 97.5 107.2 112.3 § 2,196.3 4.8 37.0 62.9 84.8 95.1 104.7 111.8 05 35 7 197.3 13.5 37.8 63.3 84.9 98.8 108.6 115.9 21 197.3 17.4 36.5 58.4 77.9 88.9 98.2 103.1 44

From the results shown in Table 13 above, there was no profound slowing of the release rate of the samples of Example 2 compared to the results of Example 1 under high temperature / high humidity conditions. This profound slowdown is evident when comparing, for example, Tables 3-8 (Example 1) with the first drug dissolution in Table 13 (Example 2) with the first drug dissolution (e.g., 0% vs. 15.6% release after one hour; 4.6% vs. 10). 43.8% after two hours; 29.5% vs. 68.7% after four hours, etc.). However, in Example 2, the drug release rate would probably be reduced to more similar values than in Example 1 when the drug was exposed to accelerated conditions. In other words, an endpoint having a dissolution profile consistent with the baseline of Example 1 is not obtained.

Example 3

Extended mixing time

Example 3 involves another attempt to stabilize hydromorphone HCl beads coated with AquacoatR-20 starting from the fact that the high temperature is not sufficient to ensure complete fusion of the ethylcellulose membrane. The FMC recommends a standard mixing time (and 25 binding) of the plasticizer and AquacoatR of 30 minutes. In Example 3, the contact time of the plasticizer (triethyl citrate) and the ethylcellulose polymer dispersion (Aquacoat) was extended to 24 hours.

The coated beads were prepared in accordance with Example 1 and then placed in a 30 cm3 amber glass flask at m 30 and cured at 60 ° C in a dry oven.

(M

x sa. Dissolution studies were then performed using tr three samples at the following times: 1 day, 2 days, c \ | 7 days and 11 days. The mean results are shown in Table 14 below.

05

Table 14 45

Dissolution (time)

Time Weight Hours (days) (mg) 1 2 4 8 12 18 24 5 1 210.7 27.7 53.3 77.3 95.7 103.4 108.2 110.4 2 209.7 25.9 50 , 3 74.3 94.2 101.9 106.4 110.2 7 209.7 24.8 48.3 73.1 95.2 102.7 108.5 112.6 11 210.3 24.0 45 , 4 70.5 94.9 103.9 113.3 115.9 10 The results presented in Table 14 above show that there was no profound slowing of the release rate of the samples of Example 3 compared to the initial results obtained in Example 1 and under high temperature / high humidity conditions. In other words, an end point at which the dissolution profile drops to the base level of Example 1 was not reached. This fundamental slowdown in release rate is evident when comparing, for example, Tables 3-8 (Example 1) with first drug dissolution after one day of storage (e.g. 0% vs. 27.7% after one hour; 4.6% vs. 53.3% after 2 hours; 29.5% vs. 77.3% after 4 hours, etc.).

Example 4

Recommended Cure (Prior Art) Hydromorphone beads were prepared by dissolving hydromorphone HCl in water, adding the Opadry® product and stirring the mixture for about 1 hour and then spraying it onto a pariel 18/20 bead using Wuster insert device. The resulting coated beads LO 30 were then coated with Opadry® Y-5-1442 pink C 1-1 (15 wt%). The beads were then coated with an aqueous dispersion of Aquacoat® product such that the bead weight in cm increased by 15% according to the following Table 15.

o co

CD

46

Table 15

Component Weight% Quantity / unit

Hydromorphone beads 84.7 80 mg

Aquacoat "CD 30 12.7 12 mg 5 CitroflexR2A (Triethyl Citrate) 2.5 2.4 mg

Total 99.9 94.4 mg

After application of the resin to the beads, the beads were cured in a fluidized bed for about 2 hours at 60 ° C as suggested in the literature and recommended by FMC because said temperature is above the glass transition temperature of AquacoatR when Aquacoat is plasticized with triethyl citrate. with a concentration of 15 at 20%.

The cured beads were then stored at room temperature for initial readout experiments and after 3 months. Samples were also stored at 37 ° C and 80% relative humidity. The mean-20 results are shown in Table 16.

Table 16 „. . Hours

Avg.

Time Weight 1 2 4 8 12 18 24 25

Beginning 283.2 30.4 44 70.2 89.1 97.0 101.3 102.1 3 Months 282.3 36.2 57.8 76.9 89.0 93.4 96.6 98.5 ^ At 37 ° C / rel. 80% ™ 1 Month 288.4 0.5 26.7 50.5 69.6 80.7 90.7 97.0 V 2 Month 287.3 0.6 25.1 50.7 70.3 81.6 92.2 98.8 c3 30 3 months 293.7 1.2 23.7 48.6 65.6 74.5 80.2 83.5 cc

From the results shown in Table 16 above, it can be seen that the dissolution profiles of the samples stored at room temperature were acceptable. However, the dissolution of the paths in display 35 was dramatically slowed down as 47 were stored at 37 ° C and 80% relative humidity. The band variation range of this example was unacceptably wide, e.g. at a one hour dissolution point (storage 37 ° C / 80% relative humidity) and at numerous other points.

Samples from the lot of Example 4 were repackaged, stored, and then exposed to heat under dry conditions at 37 ° C and humidity (37 ° C / 80% relative humidity). The solubility solutions are shown in Table 17 below.

Table 17 „,, Hours

Avg.

Time Weight 1 2 4 8. 12. 18 24.

Beginning 283.2 30.4 49.0 70.3 89.1 97.0 101.3 102.1 At 37 ° C Dry 2 weeks 283.2 25.0 44.4 65.0 84.5 92, 9 100.7 104.4 4 wk 280.7 21.5 28.0 63; 5 84.3 95.6 20Q, 37 ° C / rel. 80% 2 wk 283.2 16.6 39.1 60.5 80.1 89.8 99.8 103.4 4 wk 281.3 4.6 26.6 53.7 71.4 82.1

From the above results it appears that under dry conditions at 37 ° C, the dissolution of Example 4 did not reach the same end point as under 37 ° C and 80% relative humidity. Thus, a combination of both moisture and heat is required to complete curing.

Examples 5-7 to 30 At high temperature (60 ° C) and high humidity

(M

In order to study the effectiveness of curing in the process as an effective method for stabilizing controlled-release films made from plasticized ethylcellulose, Examples 5-7 were prepared using 05% different amounts of Aquacoat®.

48

In all Examples 5-7, hydromorphone beads were prepared according to Example 1. Subsequently, coatings in amounts of 5% by weight, 10% by weight and 15% by weight, respectively, were applied to the beads of Examples 5-7 according to the formulas shown in Tables 18-20 below.

Table 18 - Composition of Example 5 after Coating 10 Ingredient% Quantity / Unit

Hydromorphone beads 84.2 84.2 mg

AquacoatR ECD 30 4.7 4.2 mg

Triethyl citrate 0.9 0.84 mg

Total 100.0 89.24 mg 15

Table 19 - Composition of Example 6 after Coating

Component% Quantity / unit

Hydromorphone Beads 89.3 84.2 mg 20 Aquacoat R ECD 30 8.9 8.4 mg

Triethyl citrate 1.8 1.7 mg

Total 100.0 94.3 mg

Table 20 - Composition of Example 7 after Coating

Ingredient% Quantity / Unit 0 Hydromorphone Beads 84.8 84.2 mg ° AquacoatR ECD 30 12.7 12.6 mg ^ Triethyl Citrate 0.9 2.5 mg LO 30 Total 100.0 99.3 mg tr “All three batches were cured water-loaded SI drying apparatus at 60 ° C oven. These batches were placed on the sieve trays in these drying devices

σ> R

35 after the Aquacoat film was applied to an HPMC-coated 49 hydromorphone HCl bead. Dryers containing the Aquacoat® coated beads were then placed in an oven at 60 ° C for 72 hours. The lots were then removed from the furnaces. The beads looked 5 damp and were therefore dried in a laboratory line fluid bed dryer for one hour. They were then coated with 5% by weight of a 0padryR Y-5-1442 pink Wurster insert.

The stability studies of Examples 5-7 show that the first dissolutions are similar to those obtained from samples placed at 37 ° C and 80% relative humidity. The results are shown in Tables 21-23 below.

15

Table 21 - Dissolution (Time) - 5% Aquacoät Cover ν U. Hours

Avg.

Time weight 1 2 4 8 12 18 M

20 Beginning 190 39.8 57.4 73.0 88.0 93.8 98.0 95.6 28 191 33.4 54.6 71.9 84.2 89.8 94.6 96.4

Table 22 - Dissolution (Time) - 10% Aquacoat® Coat 25,. Hours

Avg.

Time Weight 1 2 4 8 JL2 18. 24.

^ Beginning 200.3 7.5 27.9 48.5 68.1 76.2 90.3 88.9 ™ 28 210 9.9 32.4 52.6 67.8 77.9 85.9 90.9 LO 30 Table 23 - Dissolution (Time) - 15% AquacoatR Coating-

CVJ

x teet cc “Hours ^ Avg.

g Time Weight 1 2 4. 8 12. 18 24.

Beginning 210 5.4, 13.9 38.0 57.8 68.4 78.6 81.3 35 28 207.3 9.5 23.8 43.4 58.8 67.8 77.0 81.3 50

Example 8

In Example 8, hydromorphone beads coated with 10% Aquacoat® were prepared according to Example 6. The hydromorphone beads of Example 8 have the preparation formula shown in Table 24 below.

Table 24

Component% Quantity / unit

Hydromorphone Beads 89.3 84.2 mg 10 Aquacoat R ECD 30 8.9 8.4 mg

Triethyl citrate 1.8 1.7 mg

Total 100.0 94.3 mg

To study the effectiveness of curing at a lower relative humidity of 15 compared to Example 6, the above beads were cured for 72 hours at 37 ° C at 60% relative humidity (instead of 85% relative humidity). The first results were similar in Example 8 as in Example 6, showing that the curing step can also be completely completed at lower relative humidity.

Table 25 - Dissolution (Time) - 10% Aquacoat® Coating 25 Example 1h 2h 4h 8h 12h 18h 24h

Ex 6 7.5 27.9 48.5 68.1 76.2 90.3 88.9 o Ex 8 1.1 18.9 45.0 65.0 76.0 85.8 91.5 δ Examples 9-10 m 30 Hydromorphone HCl beads were prepared by injection of

CM

xa suspension of hydromorphone HCl and Opadry® Y-5-1442 pink tr '(20% w / w) on Nu-pariel 18/20 beads according to the method of Example 1. These beads were then further coated with Opadry® Y-5-1442 Pink 05 (15% by weight). These beads were then coated with 51 more Surelease® products, increasing the weight of the beads by 10%. The formulation of the coated bead is shown in the following Table 26.

5 Table 26

Ingredient mg / dose%

Hydromorphone-HCl 4.0 mg 4.32 nu pariel beads 18/20 74.0 mg 79.91

Opadry Pink 6.2 mg 6.70 10% Surelease 8.4 mg 9.07

Total 92.6 mg 100.0

The batch was then divided into two portions. Example 9 was cured at 60 ° C and 85% relative humidity for 3 days (72 hours) and then dried in a fluid bed drier for 30 minutes at 60 ° C to dry excess moisture. These beads were then coated with 5% Opadry pink. Example 10 was left uncured.

The products of each of Examples 9 and 10 were then filled into hard gelatin capsules with an amount of hydromorphone 4 mg per capsule and stored for 3 months at 37 ° C and 100% relative humidity. Examples 9 and 10 were subjected to dissolution studies (following the procedure of Example 1) initially and again after 3 months of storage at 37 ° C and 100% relative humidity. The results are shown in Tables 27 and 28 below.

i. 30 Table 27 - Example 9 Time Initial 3 months at 37 ° C / rel. 100% g 1 4.7 6.5 4 42.3 56.0 05 35 8 64.9 75.0 12 77.2 83.19 52

Table 28 - Example 10

Time Beginning 3 months at 37 ° C / rel. 100% 1 1.6 4.5 5 4 12.0 61.9 8 47.8 79.0 12 66.7 87.7

The results show that, despite the expected differences in the first release rates due to the use of different aqueous dispersions of ethylcellulose (Surelease® vs. Aquacoat®), the curing step described above in Example 9 still significantly stabilizes the product compared to the uncured product of Example 10. The relatively higher controlled release rate of the examples in which the Aquacoat R coating was used compared to the Surelease R coating may be due to a lower degree of plasticization during the coating formulation. However, products using either coating can be modified to obtain satisfactory results.

Example 11

The following example illustrates the stabilization of morphine beads according to the present invention.

A suspension of morphine sulfate and HPMC (OpadryR Clear Y-5-7095) was applied to the surface of 18/20-mesh nu pa-Riel beads in a fluidized bed granulator using a Wurster insert at 60 ° C. The purple suspension of HPMC o (OpadryR Lavender YS-1-4729) τΐ was then applied as a coating at the same temperature. The beads were then coated at 60 ° C with Aquacoat®.

(M

product and triethyl citrate as plasticizer such that the weight of the beads increased by 5%. The beads were then cured in an oven at 60 ° C and 100% relative humidity for three days.

'' sf V

05 35 was dried in a fluid bed granulator at 60 ° C and the purple dye HPMC coating was then applied using a Wuster insert.

The beads were then placed in hard gelatine capsules so that the amount of morphine sulfate per capsule was 5 to 30 mg. The final formulation is shown in Table 29 below.

Table 29

Ingredient mg / capsule% 10 Morphine sulphate-5 H2O 30.0 8.51% nu pariel beads 18/20 255.0 72.36%

OpadryR Clear Y-5-7095 15.0 4.26%

Opadry ”Lavender YS-1-4729 15.8 4.48%

AquacoatR ECD30 (Solid) 15.8 4.48% 15 Triethyl Citrate 3.2 0.91%

Opadry Lavender Y-S-l-4729 17.6 1 4.99%

Total 352.4 100.00%

The first dissolution of the capsules was performed using the USP Paddle Method, 100 rpm in 900 mL of water, and again after storage for 1 month at 37 ° C and 100% RH and 60 ° C in dry . It was found that a stable product had been prepared. The results are shown in the following Table 30.

o Table 30 - Dissolved Morphine,%

w Time 37 ° C / 100% 60 ° C

A (h) Initially Relative 1 month c.

ιό 30 1 15.7 16.6 15.3 ™ 4 53.0 51.4 54.9 ^ 8 84.4 83.3 90.4 £ j 12 96.5 94.4 96.9 0 ^ Example 12 A second experiment was conducted using morphine as described in Example 11, however, a retardant was applied.

Aquacoat® layer with 15% increase in weight of product to develop slower release of morphine product. The composition of the final formulation is shown in Table 31 below.

5

Table 31

Ingredient mg / capsule%

Morphine Sulfate 5 H 2 O 30.0 7.65% nu pariel beads 18/20 255.0 65.0%> * 10 OpadryR Clear Y-5-7095 15.0 3.82%

OpadryR Lavender YS-1-4729 15.8 4.03%

Aquacoat ”ECD30 (Solid) 47.4 12.08%

Triethyl Citrate 9.5 2.42%

Opadry Lavender YSl-4729 19.6 5.00% 15 Total 392.3 100.00% 30 mg morphine sulfate capsules were first reconstituted as described in Example 10 and again after storage for one month at 37 ° C and 100% at a relative humidity of 60 ° C and dry. Again, it was found that a stable product had been prepared. The results are shown in Table 32 below.

25 Table 32 - Dissolved Morphine,%

Time 37 ° C / 100% 60 ° C

° (h) Initially relative hum.

10 3.1 0 i '^ 4 18.1 19.4 17.8 30 8 49.2 49.4 45.7 i 12 66.3 68.2 65.9

CL

Examples 13 to 14 Example 13 demonstrates the utility of another drug, theophylline, wherein said theophylline has very different physical properties compared to hydromorphone.

The aqueous theophylline and colloidal silica were first blended in a high shear mixer, then screened using a Jet sieve to improve fluidity. Using a fluidized bed granulator equipped with a rotor processor, the sugar spheres were coated with a mixture of theophylline / colloidal silica using PVP (C-90) solution. Coating was continued until a dosage of about 78% was achieved.

The formulas for the 400 mg theophylline beads filled in capsules are shown in Table 33 below.

Table 33 15 mg / unit capsules

Aqueous theophylline (equivalent to 400 mg anhydrous theophylline) 440.0

Colloidal silica 0.4

Sugar spheres, 30/35 mesh units 110.0 20 PVP (C-30) 13.5

A total of 563.9 These beads were then coated with a dibutyl sebacate plasticized AquacoatR ECD 30 retardation coating 25 with a 5% increase in bead weight in a Wurster column fluidized bed granulator. Some of the spheres were not cured and the other was stored at 60 ° C and 100% relative humidity for 72 hours. The results shown in Table 34 below were obtained.

m 30

(M

x Table 34 * Time 1 2 4 8 12 18 24 cu Beginning (size 9.0 92.8 94.6 95.4 97.8 98.0 100.0 ° C anhydrous) 35 72 hours at 60 ° C / 100% Relative Cost 3.2 5.3 7.0 7.9 11.0 14.1 35.8 56

From the foregoing, it was decided that theophylline beads coated with AquacoatR were also unstable and had to be cured. After storage for 72 hours at 60 ° C and 100% RH, a dramatic decrease in dissolution rate occurred; however, such conditions may, under some circumstances, represent "ideal" curing conditions to form a stable product. For this purpose, the dissolution data obtained after 72 hours storage at 60 ° C and 100% relative humidity produces a dissolution profile that is too slow for theophylline.

Therefore, Example 14 was prepared to improve the dissolution profile of the preparation by adding this new curing step and the coating was modified to increase the dissolution rate such that 100% theophylline dissolves within 12 hours.

Example 14 was prepared as follows. Theophylline powder coated beads were prepared as described in Example 20 in Example 13, and then coated with a plasticized AquacoatR ECD 30 retardation coating containing 10% HPMC (hydroxypropylmethylcellulose) for this example. This was done so that the release of theophylline would be faster than in Example 13. The addition of HPMC to accelerate dissolution is known in the art. The retardant layer was also coated with a 6% weight increase on the Wurster column of the fluidized bed granulator.

The coated beads were then cured for 72 hours at 60 ° C and 100% relative humidity.

(M

j. humidity at. The dissolution assay was performed initially and again after the beads were stored at 37 ° C and 80% relative humidity.

o

^ for three months. It was found that the dissolution stability of theophylline released from the preparation of Example σ> 35 14 was dramatically improved compared to Example 13. It was further observed that by adding HPMC to the retardant layer, Aquacoat R ECO 30 (solid) / HPMC = 9: 1, coated for weight gain, the dissolution rate of the 5 preparations increased so that 100% of theophylline was dissolved in 12 hours. The results are detailed in Table 35 below.

Table 35 10 Hours 1 2 4 8 12

Cured, beginning 17 38 68 97 100

Storage at 37 ° C / 80% RH 15 3 months 13 31 60 94 100

Examples 15-17

Controlled Release 8mg Hydromorphone HCl Formulations - Daily Preparation 20 Examples 15-17 were prepared as follows: 1. Drug Dosage: Hydromorphone Beads were prepared by dissolving hydromorphone HCl in water by adding Opadry® Y-5-1442 pink (product of commercially available from Colorcon, West Point, 25 Pennsylvania, PA, containing hydroxypropylmethylcellulose, hydroxypropylcellulose, titanium dioxide, polyethylene glycol, and D&C REd No. 30 aluminum lacquer) and stirring for about 1 hour to give * - 20% w / w suspension. This suspension was then sprayed onto a surface of 18/20 mesh nu pairil C 1x beads using a Wurster insert.

cc 2. First coating: The metered hydromorphone beads were then coated with an Opadry Light Pink coating so that the weight of the beads increased by 5% by weight using a Wurster insert. This coating was applied as a protective coating and produces immediate release hydromorphone beads. See Table 36 below.

Table 36 - Immediate Release Beads 5 Treatment Step Ingredient% mg / Unit Dose of Hydromorphone-HCl 4.7 4.0 nu pareil 18/20 87.9 74.0

Opadry Lt Pink 2,4 2,0 10 First Cover Opadry Lt Pink 5,0 4,2

Total 100.0 84.2 3. Retardant coating. After the first coating 15, the hydromorphone beads were then coated with a slow coating consisting of Aquacoat ECD 30 and triethyl citrate (softener) so that the weight of the beads increased by 5, 10 and 15% (based on the dry weight of the Aquacoat product). A Wurster insert was used to apply the coating suspensions.

4. Hardening. After application of the retardant coating, the beads were placed in a furnace at 60 ° C containing a water tray to maintain a relative humidity level of about 100%. All three batches were allowed to cure for 72 hours.

5. Second coating. The cured beads were removed from the moist oven and dried in a fluid bed drying machine for about one hour. The dried cured beads were then coated with an Opadry Light Pink coating of ≥ 30 so that their weight increased by 5 wt.

CM

x Wurster insert. This coating was applied as a filter coat. Details of the final bead formulations containing 5, 10 and 15% Aquacoat coating are given in the following Tables 37, 38 and 39.

σ> 59

Table 37 - Beads with 5% Coating Treatment Step Ingredient% mg / Unit Drug Dosage Hydromorphone-HCl 4.2 4.0 5 nu pareil 18/20 78.8 74.0

Opadry Lt Pink 2.1 2.0

First coating Opadry Lt Pink 4.5 4.2

Retardant coating Aquacoat ECD 30 (dry weight) 4.5 4.2

Triethyl citrate 0.9 0.8

Second coating Opadry Lt Pink 5.0 4.7

Total 100.0 93.9 15

Table 38 - Beads with 10% Coating Step of treatment Ingredient% mg / unit Drug Dosage Hydromorphone-HCl 4.0 4.0 20 nu pareil 18/20 74.5 74.0

Opadry Lt Pink 2.0 2.0

First coating Opadry Lt Pink 4.2 4.2

Retardant coating Aquacoat ECD 30 (dry weight) 8.5 8.4 0 Triethyl citrate 1.7 1.7 ^ Second coating Opadry Lt Pink 5.1 5.0

Total 100.0 99.3 m

C \ J

cc

CL

C \ l

CM

o

C/O

V

CD

60

Table 38 - Beads with 15% Coating Step of treatment Ingredient% mg / unit Drug Dosage Hydromorphone-HCl 3.8 4.0 5 nu pareil 18/20 70.8 74.0

Opadry Lt Pink 1.9 2.0

First coating Opadry Lt Pink 4.0 4.2

Retardant topcoat Aquacoat ECD 30 (dry weight) 12.1 12.6

Triethyl citrate 2.4 2.5

Second coating Opadry Lt Pink 5.0 5.2

Total 100.0 104.5 15 7. Encapsulation. The hydromorphone beads were then placed in hard gelatine capsules to give a total of 8 mg of hydromorphone HCl per capsule using the following combinations: Example 15: All beads have a 5% Aquacoat coating.

Example 16: 75% beads with 10% Aquacoat coating and 25% immediate release beads.

Example 17: 75% beads with 15% Aquacoat-25 coating and 25% immediate release beads.

Dissolution studies were performed initially and after 28 days using the Aquacoat coated hydromorphone beads of Examples 15-17. Results t— are shown in the following Tables 40-42.

m 30

CM

40 Table 40 - Dissolution of Example 15 cc

Hours g Time 1 2 4 8 12 18 24 S? Beginning 33 f 8 54.6,71.2 85.7 92.9 97.3 99.9 35 28 Days 34.0 53.1 70.8 86.1 93.1 98.2 100.7 61

Table 41 - Dissolution of Example 16

Hours

Aika I 2 4 8 12 18 24

Beginning 31.6 43.4 59.2 72.3 79.2 85.7 90.3 5 28 Days 32.3 43.7 59.2 72.6 80.7 86.8 91.5

Table 42 - Dissolution of Example 17

Hours

Time 1 2 4 8 12 18 24 10 Beginning 29.3 37.2 52.1 66.4 73.9 80.4 85.4 28 Days 31.1 37.0 51.4 66.0 73.7 81, 3 86.2

The stability studies of the Aquacoat-coated hydromorphone beads of Examples 15-17, as shown above, show that the first dissolutions are similar to those obtained from samples subjected to conditions of 37 ° C and 80% relative humidity. Examples 18 to 20 In Examples 18 to 20, a single dose, six-way randomized crossover study (one week washout) was conducted in 12 patients and the results obtained were compared with those obtained with the corresponding dose of the immediate release formulation. Blood samples were taken at the beginning of 25 and then at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 18, 24 , 30, 36, and 48 after administration of the drug to determine plasma levels. Comparative Example 18A is an 8mg hydromorphone formulation which is released immediately (two 4 x 30 4mg DilaudidR tablets, commercially available from Knoll

(M

company). Example 18 is an 8 mg dose of the Cape Hydromorphone Beads of Example 15. Example 19 is an 8 mg dose of encapsulated hydromorphone beads of Example 16. Example 20 is an 8 mg dose of the encapsulated hydromorphone ring of Example 17.

62

The results of Comparative Example 18A are shown in Figure 7. The results of Example 18 are shown in Figure 8. The results of Example 19 are shown in Figure 9. The results of Example 20 are shown in Figure 10. 5 The results of Examples 18-20 are further shown in Table 43 area under the curve (AUC) (bioavailability), peak plasma concentration (Cmax), and time to reach peak plasma concentration (tmax).

10

Table 43

Product AUC CBax Tiax

Comparative Example 18A

2 Dilaudid tablets 12427 3012 1.10 Example 18 6718 1070 2.58

Example 19 9933 1265 2.39

Example 20 8695 1138 0.88

Dilaudid is known to be effective for about 6 to 20 hours. Following administration of a 8 mg dose of Dilaudid, there was approximately 300 pg / ml hydromorphone in the blood for 6 hours. Therefore, a circulating concentration of about 300 pg / ml should be an effective analgesic concentration in the blood.

The results of Example 19 showed that the blood levels of hydromorphone were greater than 500 pg / ml at 12 hours and the blood levels were well above 300 pg / ml at 24 hours. Therefore, this product is considered suitable for i m 30 once daily administration.

(M

Example 20, on the other hand, produced concentrations greater than 300 pg / ml at 12 hours after drug administration, with concentrations of about 250 pg / ml at 24 hours after drug administration. Therefore, this product is considered to have a warfare σ> 63 suitable for twice daily use and possibly suitable for once daily administration. Example 21

In Example 21, morphine sulfate controlled release beads containing 5% by weight of a controlled release coating containing 7% HPMC as a pore former are prepared as follows.

First, the pearl product used as the starting material is manufactured using rotor process technology. The morphine sulphate 10 bead bead product to which the controlled release coating is applied has the formulation shown in Table 44 below.

Table 44 15 Component Quantity / Unit

Morphine sulfate powder 30 mg

Aqueous lactose, intact 42.5 mg PVP 2.5 mg

Sugar Beads 18/20 125 mg 20 Purified water qs

Opadry Red YS-1-1841 10.5 mg

Total 210.5 mg

A controlled release coating is prepared as follows. The pore former Methocel E5 Premium (HPMC) is dispersed and dissolved in a sufficient amount of purified water to obtain a 2% w / w solution.

The f-Aquacoat dispersion is plasticized with triethyl citrate 30 accounts for about 30 minutes. Then after 30 minutes

CM

x HPMC dispersion mixed with plasticized Aquacoat diper

CE

and the resulting mixture is stirred for a further 15-30 minutes. A dose of morphine sulfate beads is placed in a Uniglatt o ^ Wurster Insert equipped with a 1.2 mm σ> 35 fluid nozzle. The beads are then film-coated with an Aqua 64 coat / HPMC dispersion (93: 7 ratio) to increase their weight by 5%.

The formulation of the controlled release coating used in Example 21 is shown in Table 5 below.

Table 45

Component Quantity / unit

Morphine Sulfate Base Beads 210.5 mg 10 Aquacoat ECD 30 (solid) 9.8 mg

Methocel E5 Premium 0.7 mg

Triethyl citrate 2.1 mg

Purified water qs

Opadry Red YS-1-1841 11.7 mg 15 Purified water qs

Total 234.8 mg

After the controlled release coating manufacturing process was completed, the coated beads were poured from a Wurster insert onto a curing tray and cured in a temperature / humidity chamber at 60 ° C and 80% relative humidity for 72 hours. Once this curing step was completed, the beads were dried to an LOD of 4% or less and a final Opadry Red YS-1-1841 coating (15% w / w solution) was applied to them using Uniglatt Wurster Insert. The beads were then placed in hard gelatine capsules using a capsule filling device to obtain the final product.

LO 30 The final product is then subjected to a dissolution test

CM

χ using USP Apparatus II (paddle method), 100 cc rpm, 37 ° C, 700 ml of simulated gastric fluid (without enzymes) for one hour, then 900 ml of simulated gastric juice (without enzymes) after the first hour.

CD

65

The final product is then subjected to a dissolution test after being stored for 3 months and 6 months at room temperature and under accelerated storage conditions (40 ° C / 75% relative humidity) for one 5 months, two months and three months. The results are shown in Table 46 below.

Table 46 - 30 mg Morphine Sulfate Capsules with 5% Controlled Release Coating in 10 93: 7

To steal. Morphine ratio. sulphate · and test-5H20 mg / Dissolution (hours) time capsule 1_2_4_8_12_18_24.

Beginning 29 f 75 25.9 42.7 71.1 96.8 105.3 105.6 107.0 15

At room temperature for 3 months 29.63 25.0 41.2 68.2 93.0 102.7 6 months 29.64 22.8 40.4 65.7 91.5 102.9 at 40 ° C / rel. . 75% 1 month 29.33 21.9 39.1 65.9 92.9 103.0 20 '2 months 29.76 23.1 39.2 67.4 93.3 103.3 3 months 29.16 21.5 37, 6 67.5 92.8 109.2

As can be seen from the dissolution results shown in Table 46, the capsules of Example 21 produce a stable dissolution profile even after being exposed to the accelerated conditions for 3 months.

o Example 22

In Example 22, morphine sulfate? Controlled release beads are prepared having 5% w / w of a controlled release coating (including cm x 5% HPMC as a pore former, based on the weight of the coating).

An aliquot of approximately 892.4 g of morphine sulfate controlled release beads is prepared using 5 wt% of a controlled release coating and 66 of 5% HPMC coating. The morphine sulfate bead on which a controlled release coating is applied is prepared as described in Example 21. Thereafter, a controlled release coating is prepared and Levi-5 is applied to the beads. Further details of the preparation of Example 22 are shown in Table 47 below.

Table 47

Component Quantity / Unit 10 Morphine Sulfate Basic Beads 210.5 mg

Aquacoat ECD 30 (solid) 10.0 mg

Methocel E5 Premium 0.5 mg

Triethyl citrate 2.1 mg

Purified Water qs 15 Opadry Red YS-1-1841 11.7 mg

Purified water qs

A total of 234.8 mg The manufacturing process used and the curing and capsule-20 fabrication techniques are the same in Example 22 as in Example 21, except that the morphine sulfate beads are film-coated with an Aquacoat / HPMC dispersion (95: 5) in Example 22.

The following Table 48 shows the results of the dissolution experiments, in which the above experiments were carried out in the same manner as in Example 21.

0 δ

CM

m

CM

tr

CL

CM

CM

o

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Table 48 - 30 mg Morphine Sulfate Capsules with 5 H Controlled Release Coat 95: 5

To steal. Morphine 5 ratio. sulphate · and test-5H20 mg / Dissolution (hours) time capsule 1_2_4_8_12_18_24.

Beginning 30 f 38 16.9 29.6 52.3 79.8 92.8 101.4 104.7

At room temperature at 30 ° C ϊ 3 months 30.20 14.5 28.2 50.4 77.2 90.3 10 6 months 30.3 15.7 28.9 49.7 78.6 92.1 40 ° C / RH. 75% 1 month 29.84 15.9 27.1 47.7 73.8 87.4 2 months 30.72 15.5 27.4 49.6 76.6 89.0 3 months 29.95 13.9 27.4 49.8 76.6 88.9 15

As can be seen from the dissolution results shown in Table 48, the capsules of Example 22 produce a dissolution that is slower than that of Example 21. Once again, the capsules produce a stable dissolution pro-20 feeling despite being exposed to accelerated conditions.

Example 23

In Example 23, morphine sulfate controlled release beads are prepared with 5% by weight of 25 controlled release coatings (including 3% HPMC as a pore former based on the weight of the coating).

Q An aliquot of approximately 892.4 g of morphine sulfate A controlled release beads is prepared using 30% 5 wt.% Controlled release coating and

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1 3% HPMC coating. Morphine sulfate beads with a controlled release coating on the tr surface are prepared as described in Example 21. Thereafter, the controlled release coating is prepared and applied to the beads so that their weight increases by 5%.

68

Further information on the preparation of Example 23 is shown in Table 49 below.

Table 49 5 Component Quantity / Unit

Morphine Sulfate Base Beads 210.5 mg

Aquacoat ECD 30 (solid) 10.2 mg

Methocel E5 Premium 0.3 mg

Triethyl citrate 2.1 mg 10 Purified water qs

Opadry Red YS-1-1841 11.7 mg

Purified water qs

A total of 234.8 mg The manufacturing process used and the curing and encapsulation technique are the same in Example 23 as in Example 21, except that the morphine sulfate beads are film-coated with an Aquacoat / HPMC dispersion (97: 3) in Example 23.

The following Table 50 shows the results of the dissolution experiments, wherein said experiments were carried out in the same manner as in Example 21.

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Table 50 - Morphine Sulphate Controlled Release 30 mg Capsules with 5% Controlled Release Coating (97: 3 Ratio) Specified 5 Stocks. Morphine ratio. sulphate * and test 5H20 mg / Dissolution (hours) rest time capsule 1_2_4_8_12 18

Beginning 17, 8 28f4 46.7 73.1 86.0 99.0 RT 30 ° C / 60% RH 31.60 10 3 Months 17.9 27.3 44.6 71.1 86.0 99.8 400C / 75% RH 28.0 Month 1 25.64 18.3 26.4 46.9 77.0 92.9 109.7 Month 2 29.83 17.1 29.3 47.2 75.8 92.4 104.7 3 months 31.63 14.3 23.9 40.8.67.2 81.1 96.3 15 RT = room temperature RH = relative humidity 1

As can be seen from the dissolution results shown in Table 50, the capsules of Example 23 produce a dissolution rate that is slower than that of Example 21. Once again, the capsules produce a stable dissolution profile despite being exposed to accelerated conditions.

Example 24 Studies to determine human bioavailability were conducted in a controlled manner comparing 30mg morphine sulfate-releasing capsules produced in Examples 21 and 22 to the reference standard, Ά30mg MS Contin tablets marketed twice daily. as a preparation to be taken. research

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kimus was a three-way, crossover study using normal male volunteers, which included a one week clearance period and doses o pj! given under fasting conditions. The study included 15 volunteers.

70

The results of this study are summarized in Table 51 below.

Table 51 5

Measurement MS Contin Example 21 Example 22 AUC 89.31 96.24 93.85

Tmax 2.62 2.90 3.87

Cmax 10.09 7.02 5.89 1Q PW @ HH * 5.25 9.00 10.50 * Pitch width at half height

Figure 11 is a graph showing the dissolved amount of preparations (MS Contin, Example 21 and Example 22) as a percentage in vitro. Figure 12 is a graph of blood levels in volunteers for each formulation.

Figure 13 is a graph of blood concentration curves obtained using MS Contin Tablets-20 compared to the theoretical blood concentration curve that would be obtained if two capsules of Example 22 which release morphine sulfate in a controlled manner were administered simultaneously (ratio Aquacoat / HPMC). 95: 5). The curve of Example 22 (wherein the blood concentration obtained with one capsule of Example 22 is twice at each time point) indicates that the capsules of Example 22 appear to be suitable for administration to a human patient once daily. This is the most surprising result, since in vitro dissolution tests seemed to show that the preparation would only be suitable for twice daily administration (see Figure 11, which shows the dissolution curves in vitro).

Example 25c It is apparent from the information in Example 24 that the capsules of Example 22-35 (coated with 5% Aquacoat-71 coating [HPMC 95: 5] on beads) produced profiles of blood that appeared suitable for once daily drug administration. However, the data showed that reducing the amount of pore former (HPMC) slightly could result in an even better dosage preparation for once daily administration. Therefore, a human bioavailability study was conducted using the capsule produced in Example 23 containing 3% of the pore former, using the capsules of Example 22 and the 30 mg MS Contin tablets as the reference capsules. The same study also looked at the effect of dosing with food. Table 52 summarizes the results obtained.

15 Table 52

Study Group AUC Tmax C_ „

Example 24 (97: 3, fasting) 101 5.6 5.9

Example 28 (95: 5, fasting) 93 3.6 7.0

Example 24 (97: 3, with diet) 96 7.8 5.9 20 MS Contin (fasting) 103 2.3 13.0

Figure 14 produces comparative dissolution curves obtained in vitro using Example 23, Example 22 and MS Contin.

Figure 15 produces representative blood concentrations obtained after administration of the product of Example 23 and MS Contin (fasted patients) to patients (both nourished and fasted).

Fig. 16 shows the blood concentration cosmic 30 spring curve obtained using MS Contin versus the theoretical blood concentration curve cd that would be obtained if two 30 mg of Example 23 were administered simultaneously. capsules that release controlled release of morphine sulfate (Aquacoat / O ratio 35 HPMC 95: 5). The theoretical curve of Example 23 (wherein the 72 blood concentration obtained using one of the capsules of Example 23 is twice at all times) indicates that the capsules of Example 23 appear to be suitable for once daily administration to human patients.

This is the most surprising result since in vitro dissolution tests seemed to indicate that the preparation would only be suitable for twice daily dosing (see Figure 11 for in vitro dissolution curves).

Example 26 Tablets containing controlled release acetaminophen (APAP) were prepared according to the invention as follows. First, immediate release APAP cores are prepared by compressing Compap coarse L into tablet cores weighing approximately 555.6 mg. Compap kar-15 kea L contains approximately 90% APAP along with pharmaceutical grade excipients including binder, disintegrant and lubricant, and is a direct compression material commercially available from Mallinckrodt, Inc., St. Louis, MO. APAP tablet-20 cores contain approximately 500 mg of APAP. Compap coarse L is extruded using a rotary tablet press equipped with a 7/16 inch standard round concave cup, flat part, machine tool setup. The cores were pressed to a theoretical weight of 25 555.6 mg and a hardness of about 8-9 kg.

Next, the APAP tablet cores prepared above are coated with the controlled release coating of the present invention as follows. Methocel E5 premium is dispersed in hot purified water using a mixture of 30 inches of water three times by weight. Methocel E5 Premium. Purified water is then added at ambient temperature and the resulting mixture 01 is stirred for about 1 hour. The mixture is allowed to cool, and the amount of purified water added at ambient temperature is calculated such that the final coating suspension contains about 20% solid polymer and plasticizer.

In a separate container, triethyl citrate and Aquacoat ECD-30 are mixed for about 15 minutes. The Aquacoat / triethyl citrate suspension is then added

The Methocel dispersion and the resulting mixture are thoroughly mixed. A suitable number of APAP tablet cores are placed in an Accella Cota coating pan. The Aquacoat / Triethyl Citrate Coating Suspension is sprayed from a suitable shower device until a weight gain of 10% / tablet is achieved.

The following table provides additional information on controlled release APAP tablets.

15

Table 53

Ingredients mg / tablet APAP IR Tablet Core 555.6

Aquacoat ECD-30 (solid) 27.78 20 Methocel E5 premium 27.78

Triethyl Citrate 11.11

Purified water qs

Total 622.27 After the coating process was completed, the coated tablets were poured onto a curing tray and cured in a temperature / humidity chamber at 60 ° C and 80% relative humidity for 72 hours with a controlled release mold. 30 items. In vitro dissolution was performed

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x in simulated intestinal fluid at 37 ° C using the tr USP basket method at 100 rpm. The results in cm are shown in the following Table 54.

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Table 54

Hour Dissolved APAP,% 1 2.7 2 6.3 5 4 13.9 8 27.1 12 36.4 18 47.7 24 58.4 10

Example 27

Example 27 provides controlled release APAP tablets with a slower dissolution than the tablets of Example 26.

First, immediate release APAP tablet cores are prepared according to Example 26. APAP controlled release tablets are then prepared by coating the APAP tablet core cores with a controlled release coating obtained from an aqueous dispersion of ethyl cellulose containing 50% HPMC as a pore former with a 15% increase in weight of the tablet. The following table 55 shows the formulation of coated APAP tablet cores.

25

Table 55 o Ingredients mg / tablet ^ APAP IR tablet cores 555.6

Aquacoat ECD-30 (solid) 41.67 lq 30 Methocel E5 premium 41.67

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Triethyl citrate 16.67 cc

Purified water qs

A total of 655.61 o co 35 The method of preparing the coating suspension and the method of applying it to the cores are the same as that described in Example 26 75. The coating suspension is applied until the required weight gain / tablet is achieved. The coated tablets are then cured according to the methods set forth in Example 26. Next, the in-cured coated APAP controlled release formulation is dissolved in vitro in the same manner as in Example 26. The results are shown in Table 56 below.

Table 56

Hour Dissolved APAA,% 1 2.3 2 5.3 4 10.6 15 8 20.1 12 28.6 18 39.5 24 50.0 20 Example 28

In Example 28, the controlled release APAP tablet formulation of Example 26 is increased by increasing the amount of pore former. In this example, immediate release APAP tablet cores 25 are prepared according to the manufacturing method set forth in Example 26. A controlled release coating containing an aqueous dispersion of ethylcellulose containing 60% HPMC as a pore former is then applied to the immediate release APAP tablet cores.

The coating suspension is then applied to the tablet en x cores as shown in Example 26. The coating suspension is applied until the required weight gain / tab is achieved. Further details of the preparation of Example 28 are shown in Table 57 below.

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76

Table 57

Ingredients mg / tablet APAP IR Tablet Core 555.6

Aquacoat ECD-30 (solid) 22,224 5 Methocel E5 premium 33,336

Triethyl citrate 11,112

Purified water qs

Total 622,272 The tablets of Example 28 are then cured in the same manner as the tablets of Example 26. The in vitro dissolution of the cured coated tablets of Example 28 is shown in the following Table 58.

15 Table 58

Hour Dissolved APAP,% 1 3.1 2 22.4 4 79.4 20 8 100.1

Example 29

In Example 29, the dissolution rate of the tablets of Example 26 is increased by controlled increasing the amount of pore former contained in the coating to 70%.

In Example 29, immediate release tablet cores are prepared according to Production Method i, described in Example 26. The immediate release cores LO 30 are then coated with a controlled release coating x containing an aqueous dispersion of ethylcellulose, containing 70% HPMC as a pore former. The coatings are continued until a 10% weight gain is achieved.

The formulas for coated APAP tablet cores are described in the following table 59.

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Table 59

Ingredients mg / tablet APAP IR Tablet Core 555.6

Aquacoat ECD-30 (solid) 16,668 5 Methocel E5 premium 38,892

Triethyl citrate 11,112

Purified water qs

Subsequently, the coated tablets are cured under the same conditions as in Example 26. In vitro dissolution is performed as described in Example 26. The results are shown in Table 60 below.

15 Table 60

Hour Dissolved APAP,% 1 97.2 2 102.8 20 The examples produced are not intended to be exhaustive. Many other variations of this invention are likely to be apparent to those skilled in the art.

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Claims (27)

A process for obtaining a controlled release formulation of an active agent, characterized in that a variety of immediate release solid substrates are prepared which comprise a therapeutically active agent; a portion of said amount of immediate release substrate is coated with a controlled release coating, which coating originates from an aqueous dispersion of ethyl cellulose, said coated substrate is cured at a temperature greater than the glazing temperature of the aqueous dispersion of ethyl cellulose, and in a relative humidity of about 60-100%, long enough to reach the curing end point, wherein said coated substrate provides a stabilized solution of said active substance, such that the amount of active substance That is released from the coated substrates prior to exposure to accelerated storage conditions, involving at least one man at a temperature of 40 ° C and at a relative humidity of 75%, and after release, does not vary at any time of dissolution more than about 20% measured with the USP Basket Method method at 100 rpm, in 700 ml s molarized gastric fluid at pH 1.2 for the first 5 hours at 37 ° C and then in 900 ml aqueous buffer, pH 7.5, at 37 ° C; and including the coated substrates and the immediate release substrate in a capsule or tablet. 2. A process according to claim 1, characterized in that the immediate release substrates are prepared CM g by coating said therapeutically active substance on the surface of a plurality of mert beads. 3. A process according to claim 1, characterized in that said coated substrate is cured for about 48-about 72 hours. Method according to claim 1, characterized in that said coated substrate is coated, so that their weight increases about 2 - about 25%. 5. A method according to claim 1, characterized in that said therapeutically active substance is selected from a group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastrointestinal substances, substances which attenuate vomiting, epilepsy -part, vasodilators, substances that relieve cough, mucus-releasing cough medicines, asthma drugs, hormones, substances that increase urinary output, blood pressure-increasing substances, substances that lower blood pressure, substances that increase airways, steroids, home remedies, antivirals, antivirals, antivirals substances affecting the psychic functions, diarrhea, mucolytes, sedatives, congestion-reducing substances, stools, vitamins and stimulants. 6. A process according to claim 1, characterized in that said therapeutically active substance is opioid pain medicine selected from a group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, buprenorphine. , salts and mixtures of the above. 5 Process according to claim 1, characterized in that ethyl cellulose is included as an effective Y amount to release the therapeutically active substance for at least about 24 hours. g 8. A process according to claim 1, characterized in that, in addition, said controlled release CM g coating comprises a substance which changes the release, which substance is selected from a group consisting of a hydrophilic polymer, a semi-permeable polymer. , an erosion-promoting polymer, a substance which amplifies forming lamellae with micropores, a pore former, and what soin heist of the mixtures of the above. 9. A process according to claim 8, characterized in that said substance which alters the release has been selected from a group consisting of hydroxypropylmethyl cellulose, lactose, metal stearate and any of the mixtures of the above-mentioned. 10. A method according to claim 1, characterized in that ethyl cellulose is included as an effective amount to produce an effective hait of said therapeutically active substance in the blood for at least about 12 hours. 11. Process according to claim 10, characterized in that said coated substrate is cured at a temperature higher than the glazing temperature of the aqueous dispersion of the plasticized ethyl cellulose, and in a relative humidity of about 60-100%, until the individual the ethyl cellulose particles are joined together in said coating. Method according to Claim 11, characterized in that said coated substrate is cured for a time of about 48 - about 72 hours, in a relative humidity of about 85%. 13. A process according to claim 1, characterized in that said coated substrate is cured, such that the controlled release formulation produces a hostically effective level of the active substance in the blood for a period of up to 24 hours of at least 24 hours. by mouth. O 14. A method according to claim 1, characterized in that said capsule is a hard gelatin capsule. cu 30 15. A method according to claim 1, characterized in that said coated substrates and substrates which are released immediately are included in said capsule or tablet in the ratio 1: 3. co o> Method according to claim 8, characterized in that said coating contains about 0.1 - 70% of said substance which changes the release. Method according to claim 8, characterized in that said coating contains about 0.1 - 50% of said substance which changes the release. Method according to claim 8, characterized in that said coating contains about 0.1 - 25% of said substance which changes the release. 19. A method according to claim 1, characterized in that it also includes at least once in said controlled release coating. 10 20. A method according to claim 1, characterized in that said controlled release formulation produces a stabilized solution of said active substance, which solution is invariable after said product has been subjected to accelerated storage conditions, which entails a temperature of 40 ° C and a relative humidity of 75%, over 3 months. 21. Method according to claim 1, characterized in that said controlled release coating is coated with a part of said active substance. 20 Method according to claim 10, characterized in that the amount of therapeutically active substance released from the cured substrates prior to storage in accelerated storage conditions, which involves at least one manifold at a temperature of 40 ° C and a relative humidity of 75%, and after storage, does not vary more than about 15% at any given time. A method according to claim 10, characterized in that the amount of said therapeutically active substance »7 released from the cured substrates prior to storage in accelerated storage conditions, which means at least one g in a temperature of 40 ° C. and in a relative humidity of 75%, and after storage, does not vary more than about 10% at any given time. The method according to claim 2, characterized in that the immediate release substrates and the coated substrates are filled into a capsule. 25. A method according to claim 1, characterized in that the immediate release substrates and the coated substrates are pressed into a tablet. 26. A method according to claim 1, characterized in that said part is coated with the controlled release coating, such that the weight increases about 2 to 30%. Process for obtaining a controlled release formulation of an active substance, characterized in that the active substance is pressed together with a filler into an immediate release tablet core, the pressed tablet core is coated with a controlled release, which coating originates from the aqueous dispersion of the ethyl cellulose, and said coated pressed tablet core is cured at a temperature higher than the glazing temperature of the aqueous dispersion of the plasticized cellulose, and in a relative humidity of about 60-100%. long enough to reach the end point of cure, said coated tablet core producing a stabilized solution of said active substance, such that the amount of said therapeutically active substance released from the coated pressed tablet core prior to exposure to accelerated storage,which means at least one man at a temperature of 40 ° C and at a relative humidity of 75%, or after release, does not vary at any time of dissolution more than about 20%, as measured by the ^ USP Basket Method method with speed 100 rpm, Y in 700 ml of simulated gastric fluid at pH 1.2 during the first LT) cm 30 hours at 37 ° C and then in 900 ml of an aqueous Er buffer, pH 7.5, at 37 ° C. 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